Estrogen receptor modulators

ABSTRACT

The present invention relates to compounds and derivatives thereof, their synthesis, and their use as estrogen receptor modulators. The compounds of the instant invention are ligands for estrogen receptors and as such may be useful for treatment or prevention of a variety of conditions related to estrogen functioning including: bone loss, bone fractures, osteoporosis, metastatic bone disease, Paget&#39;s disease, periodontal disease, cartilage degeneration, endometriosis, uterine fibroid disease, hot flashes, increased levels of LDL cholesterol, cardiovascular disease, impairment of cognitive functioning, age-related mild cognitive impairment, cerebral degenerative disorders, restenosis, gynecomastia, vascular smooth muscle cell proliferation, obesity, incontinence, inflammation, inflammatory bowel disease, irritable bowel syndrome, sexual dysfunction, hypertension, retinal degeneration and cancer, in particular of the breast, uterus and prostate.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. Ser. No.11/792,729, filed Jun. 7, 2007 now U.S. Pat. No. 7,511,152, which claimspriority from U.S. Provisional Application Ser. No. 60/634,785, filedDec. 9, 2004.

BACKGROUND OF THE INVENTION

Naturally occurring and synthetic estrogens have broad therapeuticutility, including: relief of menopausal symptoms, treatment of acne,treatment of dysmenorrhea and dysfunctional uterine bleeding, treatmentof osteoporosis, treatment of hirsutism, treatment of prostatic cancer,treatment of hot flashes and prevention of cardiovascular disease.Because estrogen is very therapeutically valuable, there has been greatinterest in discovering compounds that mimic estrogen-like behavior inestrogen responsive tissues.

The estrogen receptor has been found to have two forms: ERα and ERβ.Ligands bind differently to these two forms, and each form has adifferent tissue specificity to binding ligands. Thus, it is possible tohave compounds that are selective for ERα or ERβ, and therefore confer adegree of tissue specificity to a particular ligand.

What is needed in the art are compounds that can produce the samepositive responses as estrogen replacement therapy without the negativeside effects. Also needed are estrogen-like compounds that exertselective effects on different tissues of the body.

The compounds of the instant invention are ligands for estrogenreceptors and as such may be useful for treatment or prevention of avariety of conditions related to estrogen functioning including: boneloss, bone fractures, osteoporosis, metastatic bone disease, Paget'sdisease, periddontal disease, cartilage degeneration, endometriosis,uterine fibroid disease, hot flashes, increased levels of LDLcholesterol, cardiovascular disease, impairment of cognitivefunctioning, age-related mild cognitive impairment, cerebraldegenerative disorders, restenosis, gynecomastia, vascular smooth musclecell proliferation, obesity, incontinence, anxiety, depression resultingfrom an estrogen deficiency, inflammation, inflammatory bowel disease,irritable bowel syndrome, sexual dysfunction, hypertension, retinaldegeneration and cancer, in particular of the breast, uterus andprostate.

SUMMARY OF THE INVENTION

The present invention relates to compound and pharmaceuticalcompositions useful for treating or preventing a variety of conditionsrelated to estrogen functioning. One embodiment of the present inventionis illustrated by treating or preventing estrogen related disorders witha compound of the following formula, and the pharmaceutically acceptablesalts and stereoisomers thereof:

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to compound and pharmaceuticalcompositions useful for treating or preventing a variety of conditionsrelated to estrogen functioning. One embodiment of the present inventionis illustrated by a compound of the following formula, and thepharmaceutically acceptable salts and stereoisomers thereof:

-   wherein X is O, N—OR^(a), N—NR^(a)R^(b) or C₁₋₆ alkylidene, wherein    said alkylidene group is optionally substituted with hydroxy, amino,    O(C₁₋₄alkyl), NH(C₁₋₄ alkyl), or N(C₁₋₄alkyl)₂;-   R¹ is hydrogen, fluoro, chloro, bromo, iodo, C₁₋₄alkyl, C₂₋₄alkenyl,    C₂₋₄alkynyl, C₃₋₆cycloalkyl, aryl or heteroaryl, wherein said alkyl,    alkenyl, alkynyl, cycloalkyl, aryl and heteroaryl groups are    optionally substituted with 1, 2 or 3 groups selected from the group    consisting of fluoro, chloro, bromo, iodo, cyano and OR^(a);-   R² is hydrogen, (C═O)R^(a), (C═O)OR^(a) or SO₂R^(a);-   R³ is hydrogen, fluoro, chloro, bromo or hydroxy;-   R⁴ is hydrogen, fluoro, chloro, bromo or hydroxy;-   or R³ and R⁴, when taken together with the carbon atom to which they    are attached, form a carbonyl group;-   R⁵ is hydrogen, fluoro, chloro or C₁₋₅alkyl, wherein said alkyl is    optionally substituted with chloro, bromo, iodo, OR^(a) or 1-5    fluoro;-   R^(a) is selected from the group consisting of hydrogen, C₁₋₄alkyl,    and phenyl, wherein said alkyl and phenyl groups are optionally    substituted with hydroxy, amino, O(C₁₋₄alkyl), NH(C₁₋₄alkyl),    N(C₁₋₄alkyl)₂, chloro, bromo or 1-5 fluoro, and when two or more    R^(a) are present, they are independently selected;-   or a pharmaceutically acceptable salt or stereoisomer thereof.

In a class of the embodiment, X is O or N—OR^(a). In a subclass of theembodiment, X is O or N—OH. In a further subclass of the embodiment, Xis O.

In a class of the embodiment, R¹ is hydrogen, fluoro, chloro, bromo, orC₁₋₄alkyl, wherein said alkyl group is optionally substituted with 1, 2or 3 groups selected from the group consisting of fluoro, chloro orbromo.

In a class of the embodiment, R² is hydrogen.

In a class of the embodiment, R³ is hydrogen.

In a class of the embodiment, R⁴ is hydrogen.

In a class of the embodiment, R⁵ is hydrogen.

Non-limiting examples of the present invention include, but are notlimited to:

-   6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one;-   6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one;-   6-bromo-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one;-   6-phenyl-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one;-   6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one    oxime;-   6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5d][1,2,3]triazol-7(8H)-one    oxime;-   6-phenyl-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one    oxime;-   (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one;-   (8R,10aS)-6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one;-   (8R,10aS)-6-bromo-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one;-   (8R,10aS)-6-phenyl-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one;-   (8R,10aS)-6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one    oxime;-   (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one    oxime;-   (8R,10aS)-6-phenyl-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one    oxime;    and the pharmaceutically acceptable salts and stereoisomers thereof.

Also included within the scope of the present invention is apharmaceutical composition which is comprised of a compound as describedabove and a pharmaceutically acceptable carrier. The invention is alsocontemplated to encompass a pharmaceutical composition which iscomprised of a pharmaceutically acceptable carrier and any of thecompounds specifically disclosed in the present application. The presentinvention also relates to methods for making the pharmaceuticalcompositions of the present invention. The present invention is alsorelated to processes and intermediates useful for making the compoundsand pharmaceutical compositions of the present invention. These andother aspects of the invention will be apparent from the teachingscontained herein.

Utilities

The compounds of the present invention are selective modulators ofestrogen receptors and are therefore useful to treat or prevent avariety of diseases and conditions related to estrogen receptorfunctioning in mammals, preferably humans.

The compounds of the present invention have advantages over similarcompounds known in the art in that they present a more desirablemetabolic profile. Drug metabolism can be observed in vitro in humanliver microsome assays, see e.g., Regina W. Wang, “Validation of(−)-N-3-benzyl-phenobarbital as a selective inhibitor of CYP2C19 inhuman liver microsomes,” DMD 32:584-586, 2004. Also, the compounds ofthe present invention have advantages over similar compounds known inthe art in that they show a more potent ERβ agonistic effect in vivo asmeasured by the level of induction of the tryptophan hydroxylase gene(see International Publication WO2004027031 to Merck & Co., Inc.).

A variety of diseases and conditions related to estrogen receptorfunctioning includes, but is not limited to, bone loss, bone fractures,osteoporosis, metastatic bone disease, Paget's disease, periodontaldisease, cartilage degeneration, endometriosis, uterine fibroid disease,hot flashes, increased levels of LDL cholesterol, cardiovasculardisease, impairment of cognitive functioning, age-related mild cognitiveimpairment, cerebral degenerative disorders, restenosis, gynecomastia,vascular smooth muscle cell proliferation, obesity, incontinence,anxiety, depression resulting from an estrogen deficiency,perimenopausal depression, postpartum depression, premenstrual syndrome,manic depression, anxiety, dementia, obsessive compulsive behavior,attention deficit disorder, sleep disorders, irritability, impulsivity,anger management, multiple sclerosis and Parkinson's disease,inflammation, inflammatory bowel disease, irritable bowel syndrome,sexual dysfunction, hypertension, retinal degeneration and cancer, inparticular of the breast, uterus and prostate. In treating suchconditions with the instantly claimed compounds, the requiredtherapeutic amount will vary according to the specific disease and isreadily ascertainable by those skilled in the art. Although bothtreatment and prevention are contemplated by the scope of the invention,the treatment of these conditions is the preferred use.

The present invention also relates to methods for eliciting an estrogenreceptor modulating effect in a mammal in need thereof by administeringthe compounds and pharmaceutical compositions of the present invention.

The present invention also relates to methods for eliciting an estrogenreceptor antagonizing effect in a mammal in need thereof byadministering the compounds and pharmaceutical compositions of thepresent invention. The estrogen receptor antagonizing effect can beeither an ERα antagonizing effect, an ERβ antagonizing effect or a mixedERα and ERβ antagonizing effect.

The present invention also relates to methods for eliciting an estrogenreceptor agonizing effect in a mammal in need thereof by administeringthe compounds and pharmaceutical compositions of the present invention.The estrogen receptor agonizing effect can be either an ERα agonizingeffect, an ERβ agonizing effect or a mixed ERα and ERβ agonizing effect.A preferred method of the present invention is eliciting an ERβagonizing effect.

The present invention also relates to methods for treating or preventingdisorders related to estrogen functioning, bone loss, bone fractures,osteoporosis, metastatic bone disease, Paget's disease, periodontaldisease, cartilage degeneration, endometriosis, uterine fibroid disease,hot flashes, increased levels of LDL cholesterol, cardiovasculardisease, impairment of cognitive functioning, age-related mild cognitiveimpairment, cerebral degenerative disorders, restenosis, gynecomastia,vascular smooth muscle cell proliferation, obesity, incontinence,anxiety, depression resulting from an estrogen deficiency, inflammation,inflammatory bowel disease, irritable bowel syndrome, sexualdysfunction, hypertension, retinal degeneration and cancer, inparticular of the breast, uterus and prostate in a mammal in needthereof by administering the compounds and pharmaceutical compositionsof the present invention. Exemplifying the invention is a method oftreating or preventing depression. Exemplifying the invention is amethod of treating or preventing anxiety. Exemplifying the invention isa method of treating or preventing hot flashes. Exemplifying theinvention is a method of treating or preventing cancer. Exemplifying theinvention is a method of treating or preventing cardiovascular disease.

An embodiment of the invention is a method for treating or preventingcancer, especially of the breast, uterus or prostate, in a mammal inneed thereof by administering the compounds and pharmaceuticalcompositions of the present invention. The utility of SERMs for thetreatment of breast, uterine or prostate cancer is known in theliterature, see T. J. Powles, “Breast cancer prevention,” Oncologist2002; 7(1):60-4; Park, W. C. and Jordan, V. C., “Selective estrogenreceptor modulators (SERMS) and their roles in breast cancerprevention.” Trends Mol Med. 2002 February; 8(2):82-8; Wolff, A. C. etal., “Use of SERMs for the adjuvant therapy of early-stage breastcancer,” Ann N Y Acad. Sci. 2001 December; 949:80-8; Hou, Y. F. et al.,“ERbeta exerts multiple stimulative effects on human breast carcinomacells,” Oncogene 2004 Jul. 29; 23(34):5799-806; Steiner, M. S. et al.,“Selective estrogen receptor modulators for the chemoprevention ofprostate cancer,” Urology 2001 April; 57(4 Suppl 1):68-72; Lai, J. S. etal., “Metastases of prostate cancer express estrogen receptor beta,”Urology 2004 October; 64(4):814-20.

Another embodiment of the invention is a method of treating orpreventing metastatic bone disease in a mammal in need thereof byadministering to the mammal a therapeutically effective amount of any ofthe compounds or pharmaceutical compositions described above. Theutility of SERMS in the treatment of metastatic bone disease is known inthe literature, see, Campisi, C. et al., “Complete resolution of breastcancer bone metastasis through the use of beta-interferon andtamoxifen,” Eur J Gynaecol Oncol 1993; 14(6):479-83.

Another embodiment of the invention is a method of treating orpreventing gynecomastia in a mammal in need thereof by administering tothe mammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The utility of SERMS in thetreatment of gynecomastia is known in the literature, see, Ribeiro, G.and Swindell R., “Adjuvant tamoxifen for male breast cancer.” Br JCancer 1992; 65:252-254; Donegan, W., “Cancer of the Male Breast,” JGSMVol. 3, Issue 4, 2000.

Another embodiment of the invention is a method of treating orpreventing post-menopausal osteoporosis, glucocorticoid osteoporosis,hypercalcemia of malignancy, bone loss and bone fractures in a mammal inneed thereof by administering to the mammal a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove. The utility of SERMs to treat or prevent osteoporosis,hypercalcemia of malignancy, bone loss or bone fractures is known in theliterature, see Jordan, V. C. et al., “Selective estrogen receptormodulation and reduction in risk of breast cancer, osteoporosis andcoronary heart disease,” Natl Cancer Inst 2001 October; 93(19): 1449-57;Bjarnason, N H et al., “Six and twelve month changes in bone turnoverare related to reduction in vertebral fracture risk during 3 years ofraloxifene treatment in postmenopausal osteoporosis,” Osteoporosis Int2001; 12(11):922-3; Fentiman I. S., “Tamoxifen protects againststeroid-induced bone loss,” Eur J Cancer 28:684-685 (1992); Rodan, G. A.et al., “Therapeutic Approaches to Bone Diseases,” Science Vol 289, 1Sep. 2000.

Another embodiment of the invention is a method of treating ofpreventing periodontal disease or tooth loss in a mammal in need thereofby administering to the mammal a therapeutically effective amount of anyof the compounds or pharmaceutical compositions described above. The useof SERMs to treat periodontal disease or tooth loss in a mammal is knownin the literature, see Rodan, G. A. et al., “Therapeutic Approaches toBone Diseases,” Science Vol 289, 1 Sep. 2000 pp. 1508-14.

Another embodiment of the invention is a method of treating ofpreventing Paget's disease in a mammal in need thereof by administeringto the mammal a therapeutically effective amount of any of the compoundsor pharmaceutical compositions described above. The use of SERMs totreat Paget's disease in a mammal is known in the literature, see Rodan,G. A. et al., “Therapeutic Approaches to Bone Diseases,” Science Vol289, 1 Sep. 2000 pp. 1508-14.

Another embodiment of the invention is a method of treating orpreventing uterine fibroid disease in a mammal in need thereof byadministering to the mammal a therapeutically effective amount of any ofthe compounds or pharmaceutical compositions described above. The use ofSERMS to treat uterine fibroids, or uterine leiomyomas, is known in theliterature, see Palomba, S., et al, “Effects of raloxifene treatment onuterine leiomyomas in postmenopausal women,” Fertil Steril. 2001 July;76(1):38-43.

Another embodiment of the invention is a method of treating orpreventing obesity in a mammal in need thereof by administering to themammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The use of SERMs to treatobesity is known in the literature, see Picard, F. et al., “Effects ofthe estrogen antagonist EM-652.HCl on energy balance and lipidmetabolism in ovariectomized rats,” Int J Obes Relat Metab Disord. 2000July; 24(7):830-40.

Another embodiment of the invention is a method of treating orpreventing cartilage degeneration, rheumatoid arthritis orosteoarthritis in a mammal in need thereof by administering to themammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The use of SERMs to treatcartilage degeneration, rheumatoid arthritis or osteoarthritis is knownin the literature, see Badger, A. M. et al., “Idoxifene, a novelselective estrogen receptor modulator, is effective in a rat model ofadjuvant-induced arthritis.” J Pharmacol Exp Ther. 1999 December;291(3): 1380-6.

Another embodiment of the invention is a method of treating orpreventing endometriosis in a mammal in need thereof by administering tothe mammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The use of SERMs to treatendometriosis is known in the art, see Steven R. Goldstein, “The Effectof SERMs on the Endometrium,” Annals of the New York Academy of Sciences949:237-242 (2001).

Another embodiment of the invention is a method of treating orpreventing urinary incontinence in a mammal in need thereof byadministering to the mammal a therapeutically effective amount of any ofthe compounds or pharmaceutical compositions described above. The use ofSERMs to treat urinary incontinence is known in the art, see, Goldstein,S. R., “Raloxifene effect on frequency of surgery for pelvic floorrelaxation,” Obstet Gynecol. 2001 July; 98(1):91-6.

Another embodiment of the invention is a method of treating orpreventing cardiovascular disease, restenosis, lowering levels of LDLcholesterol and inhibiting vascular smooth muscle cell proliferation ina mammal in need thereof by administering to the mammal atherapeutically effective amount of any of the compounds orpharmaceutical compositions described above. Estrogen appears to have aneffect on the biosynthesis of cholesterol and cardiovascular health.Statistically, the rate of occurrence of cardiovascular disease isroughly equal in postmenopausal women and men; however, premenopausalwomen have a much lower incidence of cardiovascular disease than men.Because postmenopausal women are estrogen deficient, it is believed thatestrogen plays a beneficial role in preventing cardiovascular disease.The mechanism is not well understood, but evidence indicates thatestrogen can upregulate the low density lipid (LDL) cholesterolreceptors in the liver to remove excess cholesterol. The utility ofSERMs in treating or preventing cardiovascular disease, restenosis,lowering levels of LDL cholesterol and inhibiting vascular smooth musclecell proliferation is known in the art, see Nuttall, M E et al.,“Idoxifene: a novel selective estrogen receptor modulator prevents boneloss and lowers cholesterol levels in ovariectomized rats and decreasesuterine weight in intact rats,” Endocrinology 1998 December;139(12):5224-34; Jordan, V. C. et al., “Selective estrogen receptormodulation and reduction in risk of breast cancer, osteoporosis andcoronary heart disease,” Natl Cancer Inst 2001 October; 93(19):1449-57;Guzzo J A., “Selective estrogen receptor modulators—a new age ofestrogens in cardiovascular disease?,” Clin Cardiol 2000 January; 23(1):15-7; Simoncini T, Genazzani A R., “Direct vascular effects of estrogensand selective estrogen receptor modulators,” Curr Opin Obstet Gynecol2000 June; 12(3):181-7.

Another embodiment of the invention is a method of treating orpreventing the impairment of cognitive functioning, age-related mildcognitive impairment or cerebral degenerative disorders in a mammal inneed thereof by administering to the mammal a therapeutically effectiveamount of any of the compounds or pharmaceutical compositions describedabove. In models, estrogen has been shown to have beneficial effects oncognitive functioning, such as relieving anxiety and depression andtreating or preventing Alzheimer's disease. Estrogen affects the centralnervous system by increasing cholinergic functioning, neurotrophin andneurotrophin receptor expression. Estrogen also increases glutamergicsynaptic transmission, alters amyloid precursor protein processing andprovides neuroprotection. Thus, the estrogen receptor modulators of thepresent invention could be beneficial for improving cognitivefunctioning or treating age-related mild cognitive impairment, attentiondeficit disorder, sleep disorders, irritability, impulsivity, angermanagement, multiple sclerosis and Parkinsons disease. See, Sawada, Hand Shimohama, S, “Estrogens and Parkinson disease: novel approach forneuroprotection,” Endocrine. 2003 June; 21(1):77-9; McCullough L D, andHurn, P D, “Estrogen and ischemic neuroprotection: an integrated view,”Trends Endocrinol Metab. 2003 July; 14(5):228-35; which are herebyincorporated by reference in their entirety. The utility of SERMs toprevent the impairment of cognitive functioning is known in the art, seeYaffe, K., K. Krueger, S. Sarkar, et al. 2001. Cognitive function inpostmenopausal women treated with raloxifene. N. Eng. J. Med. 344:1207-1213.

Another embodiment of the invention is a method of treating orpreventing depression in a mammal in need thereof by administering tothe mammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The utility of estrogens toprevent depression has been described in the art, see Carranza-Liram S.,Valentino-Figueroa M L, “Estrogen therapy for depression inpostmenopausal women.” Int J Gynnaecol Obstet 1999 April; 65(1):35-8.Specifically, estrogen receptor beta (ERβ) selective agonists would beuseful in the treatment of anxiety or depressive illness, includingdepression, perimenopausal depression, post-partum depression,premenstrual syndrome, manic depression, anxiety, dementia, andobsessive compulsive behavior, as either a single agent or incombination with other agents. Clinical studies have demonstrated theefficacy of the natural estrogen, 17β-estradiol, for the treatment ofvarious forms of depressive illness, see Schmidt P J, Nieman L, DanaceauM A, Tobin M B, Roca C A, Murphy J H, Rubinow D R. Estrogen replacementin perimenopause-related depression: a preliminary report. Am J ObstetGynecol 183:414-20, 2000; and Soares C N, Almeida O P, Joffe H, Cohen LS. Efficacy of estradiol for the treatment of depressive disorders inperimenopausal women: a double-blind, randomized, placebo-controlledtrial. Arch Gen Psychiatry, 58:537-8, 2001; which are herebyincorporated by reference. Bethea et al (Lu N Z, Shlaes T A, Gundlah C,Dziennis S E, Lyle R E, Bethea C L. Ovarian steroid action on tryptophanhydroxylase protein and serotonin compared to localization of ovariansteroid receptors in midbrain of guinea pigs. Endocrine 11:257-67, 1999,which is hereby incorporated by reference, have suggested that theanti-depressant activity of estrogen may be mediated via regulation ofserotonin synthesis in the serotonin containing cells concentrated inthe dorsal raphe nucleus.

Another embodiment of the invention is a method of treating orpreventing anxiety in a mammal in need thereof by administering to themammal a therapeutically effective amount of any of the compounds orpharmaceutical compositions described above. The contribution ofestrogen receptors in the modulation of emotional processes, such asanxiety has been described in the art, see Krezel, W., et al.,“Increased anxiety and synaptic plasticity in estrogen receptorbeta-deficient mice.” Proc Natl Acad Sci USA 2001 Oct. 9; 98(21):12278-82.

Another embodiment of the invention is a method of treating orpreventing inflammation, inflammatory bowel disease or irritable bowelsyndrome. Inflammatory bowel diseases, including Crohn's Disease andulceratie colitis, are chronic disorders in which the intestine (bowel)becomes inflamed, often causing recurring abdominal cramps and diarrhea.The use of estrogen receptor modulators to treat inflammation andinflammatory bowel disease has been described in the art, see Harris, H.A. et al., “Evaluation of an Estrogen Receptor-β Agonist in AnimalModels of Human Disease,” Endocrinology, Vol. 144, No. 10 4241-4249.

Another embodiment of the invention is a method of treating orpreventing hypertension. Estrogen receptor beta has been reported tohave a role in the regulation of vascular function and blood pressure,see Zhu, et al., “Abnormal Vascular Function and Hypertension in MiceDeficient in Estrogen Receptor β,” Science, Vol 295, Issue 5554,505-508, 18 Jan. 2002.

Another embodiment of the invention is a method of treating orpreventing sexual dysfunction in males or females. The use of estrogenreceptor modulators to treat sexual dysfunction has been described inthe art, see Baulieu, E. et al., “Dehydroepiandrosterone (DHEA), DHEAsulfate, and aging: Contribution of the DHEAge Study to ascociobiomedical issue,” PNAS, Apr. 11, 2000, Vol. 97, No. 8, 4279-4282;Spark, Richard F., “Dehydroepiandrosterone: a springboard hormone forfemale sexuality,” Fertility and Sterility, Vol. 77, No. 4, Suppl 4,April 2002, S19-25.

Another embodiment of the invention is a method of treating orpreventing retinal degeneration. Estrogen has been shown to have abeneficial effect of reducing the risk of advanced types of age-relatedmaculopathy, see Snow, K. K., et al., “Association between reproductiveand hormonal factors and age-related maculopathy in postmenopausalwomen,” American Journal of Ophthalmology, Vol. 134, Issue 6, December2002, pp. 842-48.

Exemplifying the invention is the use of any of the compounds describedabove in the preparation of a medicament for the treatment or preventionof bone loss, bone fractures, osteoporosis, metastatic bone disease,Paget's disease, periodontal disease, cartilage degeneration,endometriosis, uterine fibroid disease, hot flashes, cardiovasculardisease, impairment of cognitive functioning, cerebral degenerativedisorders, restenosis, gynecomastia, vascular smooth muscle cellproliferation, obesity, incontinence, anxiety, depression,perimenopausal depression, post-partum depression, premenstrualsyndrome, manic depression, anxiety, dementia, obsessive compulsivebehavior, attention deficit disorder, sleep disorders, irritability,impulsivity, anger management, multiple sclerosis and Parkinson'sdisease, inflammation, inflammatory bowel disease, irritable bowelsyndrome, sexual dysfunction, hypertension, retinal degeneration or anestrogen dependent cancer, in a mammal in need thereof.

The compounds of this invention may be administered to mammals,preferably humans, either alone or, preferably, in combination withpharmaceutically acceptable carriers or diluents, optionally with knownadjuvants, such as alum, in a pharmaceutical composition, according tostandard pharmaceutical practice. The compounds can be administeredorally or parenterally, including the intravenous, intramuscular,intraperitoneal, subcutaneous, rectal and topical routes ofadministration.

In the case of tablets for oral use, carriers which are commonly usedinclude lactose and corn starch, and lubricating agents, such asmagnesium stearate, are commonly added. For oral administration incapsule form, useful diluents include lactose and dried corn starch. Fororal use of a therapeutic compound according to this invention, theselected compound may be administered, for example, in the form oftablets or capsules, or as an aqueous solution or suspension. For oraladministration in the form of a tablet or capsule, the active drugcomponent can be combined with an oral, non-toxic, pharmaceuticallyacceptable, inert carrier such as lactose, starch, sucrose, glucose,methyl cellulose, magnesium stearate, dicalcium phosphate, calciumsulfate, mannitol, sorbitol and the like; for oral administration inliquid form, the oral drug components can be combined with any oral,non-toxic, pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders includestarch, gelatin, natural sugars such as glucose or beta-lactose, cornsweeteners, natural and synthetic gums such as acacia, tragacanth orsodium alginate, carboxymethylcellulose, polyethylene glycol, waxes andthe like. Lubricants used in these dosage forms include sodium oleate,sodium stearate, magnesium stearate, sodium benzoate, sodium acetate,sodium chloride and the like. Disintegrators include, withoutlimitation, starch, methyl cellulose, agar, bentonite, xanthan gum andthe like. When aqueous suspensions are required for oral use, the activeingredient is combined with emulsifying and suspending agents. Ifdesired, certain sweetening or flavoring agents may be added. Forintramuscular, intraperitoneal, subcutaneous and intravenous use,sterile solutions of the active ingredient are usually prepared, and thepH of the solutions should be suitably adjusted and buffered. Forintravenous use, the total concentration of solutes should be controlledin order to render the preparation isotonic.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxy-ethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polyactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

The instant compounds are also useful in combination with known agentsuseful for treating or preventing bone loss, bone fractures,osteoporosis, metastatic bone disease, Paget's disease, periodontaldisease, cartilage degeneration, endometriosis, uterine fibroid disease,hot flashes, increased levels of LDL cholesterol, cardiovasculardisease, impairment of cognitive functioning, age-related mild cognitiveimpairment, cerebral degenerative disorders, restenosis, gynecomastia,vascular smooth muscle cell proliferation, obesity, incontinence,anxiety, depression resulting from an estrogen deficiency, inflammation,inflammatory bowel disease, irritable bowel syndrome, sexualdysfunction, hypertension, retinal degeneration and cancer, inparticular of the breast, uterus and prostate. Combinations of thepresently disclosed compounds with other agents useful in treating orpreventing the disorders disclosed herein are within the scope of theinvention. A person of ordinary skill in the art would be able todiscern which combinations of agents would be useful based on theparticular characteristics of the drugs and the disease involved. Suchagents include the following: an organic bisphosphonate; a cathepsin Kinhibitor; an estrogen or an estrogen receptor modulator; an androgenreceptor modulator; an inhibitor of osteoclast proton ATPase; aninhibitor of HMG-CoA reductase; an integrin receptor antagonist; anosteoblast anabolic agent, such as PTH; calcitonin; Vitamin D or asynthetic Vitamin D analogue; selective serotonin reuptake inhibitors(SSRIs); an aromatase inhibitor; and the pharmaceutically acceptablesalts and mixtures thereof. A preferred combination is a compound of thepresent invention and an organic bisphosphonate. Another preferredcombination is a compound of the present invention and a cathepsin Kinhibitor. Another preferred combination is a compound of the presentinvention and an estrogen. Another preferred combination is a compoundof the present invention and an androgen receptor modulator. Anotherpreferred combination is a compound of the present invention and anosteoblast anabolic agent.

“Organic bisphosphonate” includes, but is not limited to, compounds ofthe chemical formula

wherein n is an integer from 0 to 7 and wherein A and X areindependently selected from the group consisting of H, OH, halogen, NH₂,SH, phenyl, C₁₋₃₀ alkyl, C₃₋₃₀ branched or cycloalkyl, bicyclic ringstructure containing two or three N, C₁₋₃₀ substituted alkyl, C₁₋₁₀alkyl substituted NH₂, C₃₋₁₀ branched or cycloalkyl substituted NH₂,C₁₋₁₀ dialkyl substituted NH₂, C₁₋₁₀ alkoxy, C₁₋₁₀ alkyl substitutedthio, thiophenyl, halophenylthio, C₁₋₁₀ alkyl substituted phenyl,pyridyl, furanyl, pyrrolidinyl, imidazolyl, imidazopyridinyl, andbenzyl, such that both A and X are not selected from H or OH when n is0; or A and X are taken together with the carbon atom or atoms to whichthey are attached to form a C₃₋₁₀ ring.

In the foregoing chemical formula, the alkyl groups can be straight,branched, or cyclic, provided sufficient atoms are selected for thechemical formula. The C₁₋₃₀ substituted alkyl can include a wide varietyof substituents, nonlimiting examples which include those selected fromthe group consisting of phenyl, pyridyl, furanyl, pyrrolidinyl,imidazonyl, NH₂, C₁₋₁₀ alkyl or dialkyl substituted NH₂, OH, SH, andC₁₋₁₀ alkoxy.

The foregoing chemical formula is also intended to encompass complexcarbocyclic, aromatic and hetero atom structures for the A or Xsubstituents, nonlimiting examples of which include naphthyl, quinolyl,isoquinolyl, adamantyl, and chlorophenylthio.

Pharmaceutically acceptable salts and derivatives of the bisphosphonatesare also useful herein. Non-limiting examples of salts include thoseselected from the group consisting alkali metal, alkaline metal,ammonium, and mono-, di-, tri-, or tetra-C₁₋₃₀ alkyl-substitutedammonium. Preferred salts are those selected from the group consistingof sodium, potassium, calcium, magnesium, and ammonium salts. Morepreferred are sodium salts. Non-limiting examples of derivatives includethose selected from the group consisting of esters, hydrates, andamides.

It should be noted that the terms “bisphosphonate” and“bisphosphonates”, as used herein in referring to the therapeutic agentsof the present invention are meant to also encompass diphosphonates,biphosphonic acids, and diphosphonic acids, as well as salts andderivatives of these materials. The use of a specific nomenclature inreferring to the bisphosphonate or bisphosphonates is not meant to limitthe scope of the present invention, unless specifically indicated.

Nonlimiting examples of bisphosphonates include alendronate,cimadronate, clodronate, etidronate, ibandronate, incadronate,minodronate, neridronate, olpadronate, pamidronate, piridronate,risedronate, tiludronate, and zolendronate, and pharmaceuticallyacceptable salts and esters thereof. A particularly preferredbisphosphonate is alendronate, especially a sodium, potassium, calcium,magnesium or ammonium salt of alendronic acid. Exemplifying thepreferred bisphosphonate is a sodium salt of alendronic acid, especiallya hydrated sodium salt of alendronic acid. The salt can be hydrated witha whole number of moles of water or non whole numbers of moles of water.Further exemplifying the preferred bisphosphonate is a hydrated sodiumsalt of alendronic acid, especially when the hydrated salt isalendronate monosodium trihydrate.

The precise dosage of the organic bisphosphonate will vary with thedosing schedule, the particular bisphosphonate chosen, the age, size,sex and condition of the mammal or human, the nature and severity of thedisorder to be treated, and other relevant medical and physical factors.For humans, an effective oral dose of bisphosphonate is typically fromabout 1.5 to about 6000 μg/kg body weight and preferably about 10 toabout 2000 μg/kg of body weight. In alternative dosing regimens, thebisphosphonate can be administered at intervals other than daily, forexample once-weekly dosing, twice-weekly dosing, biweekly dosing, andtwice-monthly dosing. In a once weekly dosing regimen, alendronatemonosodium trihydrate would be administered at dosages of 35 mg/week or70 mg/week. The bisphosphonates may also be administered monthly, eversix months, yearly or even less frequently, see WO 01/97788 (publishedDec. 27, 2001) and WO 01/89494 (published Nov. 29, 2001).

“Estrogen” includes, but is not limited to naturally occurring estrogens[7-estradiol (E₂), estrone (E₁), and estriol (E₃)], synthetic conjugatedestrogens, oral contraceptives and sulfated estrogens. See, Gruber C J,Tschugguel W, Schneeberger C, Huber J C., “Production and actions ofestrogens” N Engl J Med 2002 Jan. 31; 346(5):340-52.

“Estrogen receptor modulators” refers to compounds which interfere orinhibit the binding of estrogen to the receptor, regardless ofmechanism. Examples of estrogen receptor modulators include, but are notlimited to, estrogen, progestogen, estradiol, droloxifene, raloxifene,lasofoxifene, TSE-424, tamoxifen, idoxifene, LY353381, LY117081,toremifene, fulvestrant,4-[7-(2,2-dimethyl-1-oxopropoxy-4-methyl-2-[4-[2-(1-piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2-dimethylpropanoate,4,4′-dihydroxybenzophenone-2,4-dinitrophenyl-hydrazone, and SH646.

“Cathepsin K inhibitors” refers to compounds which interfere with theactivity of the cysteine protease cathepsin K. Nonlimiting examples ofcathepsin K inhibitors can be found in PCT publications WO 00/55126 toAxys Pharmaceuticals and WO 01/49288 to Merck Frosst Canada & Co. andAxys Pharmaceuticals.

“Androgen receptor modulators” refers to compounds which interfere orinhibit the binding of androgens to the receptor, regardless ofmechanism. Examples of androgen receptor modulators include finasterideand other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide,liarozole, and abiraterone acetate.

“An inhibitor of osteoclast proton ATPase” refers to an inhibitor of theproton ATPase, which is found on the apical membrane of the osteoclast,and has been reported to play a significant role in the bone resorptionprocess. This proton pump represents an attractive target for the designof inhibitors of bone resorption which are potentially useful for thetreatment and prevention of osteoporosis and related metabolic diseases.See C. Farina et al., “Selective inhibitors of the osteoclast vacuolarproton ATPase as novel bone antiresorptive agents,” DDT, 4: 163-172(1999), which is hereby incorporated by reference in its entirety.

“HMG-CoA reductase inhibitors” refers to inhibitors of3-hydroxy-3-methylglutaryl-CoA reductase. Compounds which haveinhibitory activity for HMG-CoA reductase can be readily identified byusing assays well-known in the art. For example, see the assaysdescribed or cited in U.S. Pat. No. 4,231,938 at col. 6, and WO 84/02131at pp. 30-33. The terms “HMG-CoA reductase inhibitor” and “inhibitor ofHMG-CoA reductase” have the same meaning when used herein.

Examples of HMG-CoA reductase inhibitors that may be used include butare not limited to lovastatin (MEVACOR®; see U.S. Pat. Nos. 4,231,938,4,294,926 and 4,319,039), simvastatin (ZOCOR® see U.S. Pat. Nos.4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S.Pat. Nos. 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589),fluvastatin (LESCOL® see U.S. Pat. Nos. 5,354,772, 4,911,165, 4,929,437,5,189,164, 5,118,853, 5,290,946 and 5,356,896), atorvastatin (LIPITOR®;see U.S. Pat. Nos. 5,273,995, 4,681,893, 5,489,691 and 5,342,952) andcerivastatin (also known as rivastatin and BAYCHOL® see U.S. Pat. No.5,177,080). The structural formulas of these and additional HMG-CoAreductase inhibitors that may be used in the instant methods aredescribed at page 87 of M. Yalpani, “Cholesterol Lowering Drugs”,Chemistry & Industry, pp. 85-89 (5 Feb. 1996) and U.S. Pat. Nos.4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as usedherein includes all pharmaceutically acceptable lactone and open-acidforms (i.e., where the lactone ring is opened to form the free acid) aswell as salt and ester forms of compounds which have HMG-CoA reductaseinhibitory activity, and therefor the use of such salts, esters,open-acid and lactone forms is included within the scope of thisinvention. An illustration of the lactone portion and its correspondingopen-acid form is shown below as structures I and II.

In HMG-CoA reductase inhibitors where an open-acid form can exist, saltand ester forms may preferably be formed from the open-acid, and allsuch forms are included within the meaning of the term “HMG-CoAreductase inhibitor” as used herein. Preferably, the HMG-CoA reductaseinhibitor is selected from lovastatin and simvastatin, and mostpreferably simvastatin. Herein, the term “pharmaceutically-acceptablesalts” with respect to the HMG-CoA reductase inhibitor shall meannon-toxic salts of the compounds employed in this invention which aregenerally prepared by reacting the free acid with a suitable organic orinorganic base, particularly those formed from cations such as sodium,potassium, aluminum, calcium, lithium, magnesium, zinc andtetramethylammonium, as well as those salts formed from amines such asammonia, ethylenediamine, N-methylglucamine, lysine, arginine,ornithine, choline, N,N′-dibenzylethylenediamine, chloroprocaine,diethanolamine, procaine, N-benzylphenethylamine,1-p-chlorobenzyl-2-pyrrolidine-1′-yl-methylbenz-imidazole, diethylamine,piperazine, and tris(hydroxymethyl)aminomethane. Further examples ofsalt forms of HMG-CoA reductase inhibitors may include, but arenot-limited to, acetate, benzenesulfonate, benzoate, bicarbonate,bisulfate, bitartrate, borate, bromide, calcium edetate, camsylate,carbonate, chloride, clavulanate, citrate, dihydrochloride, edetate,edisylate, estolate, esylate, fumarate, gluceptate, gluconate,glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine,hydrobromide, hydrochloride, hydroxynapthoate, iodide, isothionate,lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate,methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, pamoate,palmitate, panthothenate, phosphate/diphosphate, polygalacturonate,salicylate, stearate, subacetate, succinate, tannate, tartrate,teoclate, tosylate, triethiodide, and valerate.

Ester derivatives of the described HMG-CoA reductase inhibitor compoundsmay act as prodrugs which, when absorbed into the bloodstream of awarm-blooded animal, may cleave in such a manner as to release the drugform and permit the drug to afford improved therapeutic efficacy.

As used above, “integrin receptor antagonists” refers to compounds whichselectively antagonize, inhibit or counteract binding of a physiologicalligand to the α_(v)β₃ integrin, to compounds which selectivelyantagonize, inhibit or counteract binding of a physiological ligand tothe α_(v)β₅ integrin, to compounds which antagonize, inhibit orcounteract binding of a physiological ligand to both the α_(v)β₃integrin and the α_(v)β₅ integrin, and to compounds which antagonize,inhibit or counteract the activity of the particular integrin(s)expressed on capillary endothelial cells. The term also refers toantagonists of the α_(v)β₆, α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄integrins. The term also refers to antagonists of any combination ofα_(v)β₃, α_(v)β₅, α_(v)β₆, α_(v)β₈, α₁β₁, α₂β₁, α₅β₁, α₆β₁ and α₆β₄integrins. H. N. Lode and coworkers in PNAS USA 96: 1591-1596 (1999)have observed synergistic effects between an antiangiogenic αv integrinantagonist and a tumor-specific antibody-cytokine (interleukin-2) fusionprotein in the eradication of spontaneous tumor metastases. Theirresults suggested this combination as having potential for the treatmentof cancer and metastatic tumor growth. α_(v)β₃ integrin receptorantagonists inhibit bone resorption through a new mechanism distinctfrom that of all currently available drugs. Integrins are heterodimerictransmembrane adhesion receptors that mediate cell-cell and cell-matrixinteractions. The α and β integrin subunits interact non-covalently andbind extracellular matrix ligands in a divalent cation-dependent manner.The most abundant integrin on osteoclasts is α_(v)β₃ (>10⁷/osteoclast),which appears to play a rate-limiting role in cytoskeletal organizationimportant for cell migration and polarization. The α_(v)β₃ antagonizingeffect is selected from inhibition of bone resorption, inhibition ofrestenosis, inhibition of macular degeneration, inhibition of arthritis,and inhibition of cancer and metastatic growth.

“An osteoblast anabolic agent” refers to agents that build bone, such asPTH. The intermittent administration of parathyroid hormone (PTH) or itsamino-terminal fragments and analogues have been shown to prevent,arrest, partially reverse bone loss and stimulate bone formation inanimals and humans. For a discussion refer to D. W. Dempster et al.,“Anabolic actions of parathyroid hormone on bone,” Endocr Rev 14:690-709 (1993). Studies have demonstrated the clinical benefits ofparathyroid hormone in stimulating bone formation and thereby increasingbone mass and strength. Results were reported by R M Neer et al., in NewEng J Med 344 1434-1441 (2001).

In addition, parathyroid hormone-related protein fragments or analogues,such as PTHrP-(1-36) have demonstrated potent anticalciuric effects [seeM. A. Syed et al., “Parathyroid hormone-related protein-(1-36)stimulates renal tubular calcium reabsorption in normal humanvolunteers: implications for the pathogenesis of humoral hypercalcemiaof malignancy,” JCEM 86: 1525-1531 (2001)] and may also have potentialas anabolic agents for treating osteoporosis.

Calcitonin is a 32 amino acid peptide produced primarily by the thyroidwhich is known to participate in calcium and phosphorus metabolism.Calcitonin suppresses resorption of bone by inhibiting the activity ofosteoclasts. Thus, calcitonin can allow osteoblasts to work moreeffectively and build bone.

“Vitamin D” includes, but is not limited to, vitamin D₃(cholecalciferol) and vitamin D₂ (ergocalciferol), which are naturallyoccurring, biologically inactive precursors of the hydroxylatedbiologically active metabolites of vitamin D: 1α-hydroxy vitamin D;25-hydroxy vitamin D, and 1α,25-dihydroxy vitamin D. Vitamin D₂ andvitamin D₃ have the same biological efficacy in humans. When eithervitamin D₂ or D₃ enters the circulation, it is hydroxylated bycytochrome P₄₅₀-vitamin D-25-hydroxylase to give 25-hydroxy vitamin D.The 25-hydroxy vitamin D metabolite is biologically inert and is furtherhydroxylated in the kidney by cytochrome P450-monooxygenase, 25 (OH)D-1α-hydroxylase to give 1,25-dihydroxy vitamin D. When serum calciumdecreases, there is an increase in the production of parathyroid hormone(PTH), which regulates calcium homeostasis and increases plasma calciumlevels by increasing the conversion of 25-hydroxy vitamin D to1,25-dihydroxy vitamin D.

1,25-dihydroxy vitamin D is thought to be responsible for the effects ofvitamin D on calcium and bone metabolism. The 1,25-dihydroxy metaboliteis the active hormone required to maintain calcium absorption andskeletal integrity. Calcium homeostasis is maintained by 1,25 dihydroxyvitamin D by inducing monocytic stem cells to differentiate intoosteoclasts and by maintaining calcium in the normal range, whichresults in bone mineralization by the deposition of calciumhydroxyapatite onto the bone surface, see Holick, M F, Vitamin Dphotobiology, metabolism, and clinical applications, In: DeGroot L,Besser H, Burger H G, eg al., eds. Endocrinology, 3^(rd) ed., 990-1013(1995). However, elevated levels of 1α,25-dihydroxy vitamin D₃ canresult in an increase of calcium concentration in the blood and in theabnormal control of calcium concentration by bone metabolism, resultingin hypercalcemia. 1α,25-dihydroxy vitamin D₃ also indirectly regulatesosteoclastic activity in bone metabolism and elevated levels may beexpected to increase excessive bone resorption in osteoporosis.

“Synthetic vitamin D analogues” includes non-naturally occurringcompounds that act like vitamin D.

Selective Serotonin Reuptake Inhibitors act by increasing the amount ofserotonin in the brain. SSRIs have been used successfully for a decadein the United States to treat depression. Non-limiting examples of SSRIsinclude fluoxetine, paroxetine, sertraline, citalopram, and fluvoxamine.SSRIs are also being used to treat disorders related to estrogenfunctioning, such as premenstrual syndrome and premenstrual dysmorphicdisorder. See Sundstrom-Poromaa I, Bixo M, Bjorn I, Nordh O.,“Compliance to antidepressant drug therapy for treatment of premenstrualsyndrome,” J Psychosom Obstet Gynaecol 2000 December; 21(4):205-11.

As used herein the term “aromatase inhibitor” includes compounds capableof inhibiting aromatase, for example commercially available inhibitorssuch as: aminoglutemide (CYTANDREN®), Anastrazole (ARIMIDEX®), Letrozole(FEMARA®), Formestane (LENATRON®), Exemestane (AROMASIN®), Atamestane(1-methylandrosta-1,4-diene-3,17-dione), Fadrozole(4-(5,6,7,8-Tetrahydroimidazo[1,5-a]pyridin-5-yl)-benzonitrile,monohydrochloride), Finrozole(4-(3-(4-Fluorophenyl)-2-hydroxy-1-(1H-1,2,4-triazol-1-yl)-propyl)-benzonitrile),Vorozole(6-[(4-chlorophenyl)-1H-1,2,4-triazol-1-ylmethyl]-1-methyl-1H-benzotriazole),YM-511 (4-[N-(4-bromobenzyl)-N-(4-cyanophenyl)amino]-4H-1,2,4-triazole)and the like.

If formulated as a fixed dose, such combination products employ thecompounds of this invention within the dosage range described below andthe other pharmaceutically active agent(s) within its approved dosagerange. Compounds of the instant invention may alternatively be usedsequentially with known pharmaceutically acceptable agent(s) when acombination formulation is inappropriate.

The term “administration” and variants thereof (e.g., “administering” acompound) in reference to a compound of the invention means introducingthe compound or a prodrug of the compound into the system of the animalin need of treatment. When a compound of the invention or prodrugthereof is provided in combination with one or more other active agents(e.g., a bisphosphonate, etc.), “administration” and its variants areeach understood to include concurrent and sequential introduction of thecompound or prodrug thereof and other agents. The present inventionincludes within its scope prodrugs of the compounds of this invention.In general, such prodrugs will be functional derivatives of thecompounds of this invention which are readily convertible in vivo intothe required compound. Thus, in the methods of treatment of the presentinvention, the term “administering” shall encompass the treatment of thevarious conditions described with the compound specifically disclosed orwith a compound which may not be specifically disclosed, but whichconverts to the specified compound in vivo after administration to thepatient. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in “Design ofProdrugs,” ed. H. Bundgaard, Elsevier, 1985, which is incorporated byreference herein in its entirety. Metabolites of these compounds includeactive species produced upon introduction of compounds of this inventioninto the biological milieu.

The present invention also encompasses a pharmaceutical compositionuseful in the treatment of the diseases mentioned herein, comprising theadministration of a therapeutically effective amount of the compounds ofthis invention, with or without pharmaceutically acceptable carriers ordiluents. Suitable compositions of this invention include aqueoussolutions comprising compounds of this invention and pharmacologicallyacceptable carriers, e.g., saline, at a pH level, e.g., 7.4. Thesolutions may be introduced into a patient's bloodstream by local bolusinjection.

When a compound according to this invention is administered into a humansubject, the daily dosage will normally be determined by the prescribingphysician with the dosage generally varying according to the age,weight, and response of the individual patient, as well as the severityof the patient's symptoms.

In one exemplary application, a suitable amount of compound isadministered to a mammal undergoing treatment. Oral dosages of thepresent invention, when used for the indicated effects, will rangebetween about 0.01 mg per kg of body weight per day (mg/kg/day) to about100 mg/kg/day, preferably 0.01 to 10 mg/kg/day, and most preferably 0.1to 5.0 mg/kg/day. For oral administration, the compositions arepreferably provided in the form of tablets containing 0.01, 0.05, 0.1,0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100 and 500 milligrams ofthe active ingredient for the symptomatic adjustment of the dosage tothe patient to be treated. A medicament typically contains from about0.01 mg to about 500 mg of the active ingredient, preferably, from about1 mg to about 100 mg of active ingredient. Intravenously, the mostpreferred doses will range from about 0.1 to about 10 mg/kg/minuteduring a constant rate infusion. Advantageously, compounds of thepresent invention may be administered in a single daily dose, or thetotal daily dosage may be administered in divided doses of two, three orfour times daily. Furthermore, preferred compounds for the presentinvention can be administered in intranasal form via topical use ofsuitable intranasal vehicles, or via transdermal routes, using thoseforms of transdermal skin patches well known to those of ordinary skillin the art. To be administered in the form of a transdermal deliverysystem, the dosage administration will, of course, be continuous ratherthan intermittent throughout the dosage regimen.

The compounds of the present invention can be used in combination withother agents useful for treating estrogen-mediated conditions. Theindividual components of such combinations can be administeredseparately at different times during the course of therapy orconcurrently in divided or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly. It will be understood that the scope ofcombinations of the compounds of this invention with other agents usefulfor treating cathepsin-mediated conditions includes in principle anycombination with any pharmaceutical composition useful for treatingdisorders related to estrogen functioning.

The scope of the invention therefore encompasses the use of theinstantly claimed compounds in combination with a second agent selectedfrom: an organic bisphosphonate; a cathepsin K inhibitor; an estrogen;an estrogen receptor modulator; an androgen receptor modulator; aninhibitor of osteoclast proton ATPase; an inhibitor of HMG-CoAreductase; an integrin receptor antagonist; an osteoblast anabolicagent; calcitonin; Vitamin D; a synthetic Vitamin D analogue; aselective serotonin reuptake inhibitor; an aromatase inhibitor; and thepharmaceutically acceptable salts and mixtures thereof.

These and other aspects of the invention will be apparent from theteachings contained herein.

DEFINITIONS

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts.

The term “therapeutically effective amount” as used herein means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue, system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician.

The terms “treating” or “treatment” of a disease as used hereinincludes: preventing the disease, i.e. causing the clinical symptoms ofthe disease not to develop in a mammal that may be exposed to orpredisposed to the disease but does not yet experience or displaysymptoms of the disease; inhibiting the disease, i.e., arresting orreducing the development of the disease or its clinical symptoms; orrelieving the disease, i.e., causing regression of the disease or itsclinical symptoms.

The term “bone resorption,” as used herein, refers to the process bywhich osteoclasts degrade bone.

The term “alkyl” shall mean a substituting univalent group derived byconceptual removal of one hydrogen atom from a straight orbranched-chain acyclic saturated hydrocarbon (i.e., —CH₃, —CH₂CH₃,—CH₂CH₂CH₃, —CH(CH₃)₂, —CH₂CH₂CH₂CH₃, —CH₂CH(CH₃)₂, —C(CH₃)₃, etc.).

The term “alkenyl” shall mean a substituting univalent group derived byconceptual removal of one hydrogen atom from a straight orbranched-chain acyclic unsaturated hydrocarbon (i.e., —CH═CH₂,—CH═CHCH₃, —C═C(CH₃)₂, —CH₂CH═CH₂, etc.).

The term “alkynyl” shall mean a substituting univalent group derived byconceptual removal of one hydrogen atom from a straight orbranched-chain acyclic unsaturated hydrocarbon containing acarbon-carbon triple bond (i.e., —C≡CH, —C≡CCH₃, —C≡CCH(CH₃)₂, —CH₂C≡CH,etc.).

The term “alkylidene” shall mean a substituting bivalent group derivedfrom a straight or branched-chain acyclic saturated hydrocarbon byconceptual removal of two hydrogen atoms from the same carbon atom(i.e., ═CH₂, ═CHCH₃, ═C(CH₃)₂, etc.).

The term “cycloalkyl” shall mean a substituting univalent group derivedby conceptual removal of one hydrogen atom from a saturated monocyclichydrocarbon (i.e., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, orcycloheptyl).

The term “aryl” as used herein refers to a substituting univalent groupderived by conceptual removal of one hydrogen atom from a monocyclic orbicyclic aromatic hydrocarbon. Examples of aryl groups are phenyl,indenyl, and naphthyl.

The term “heteroaryl” as used herein refers to a substituting univalentgroup derived by the conceptual removal of one hydrogen atom from amonocyclic or bicyclic aromatic ring system containing 1, 2, 3, or 4heteroatoms selected from N, O, or S. Examples of heteroaryl groupsinclude, but are not limited to, pyrrolyl, furyl, thienyl, imidazolyl,pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, pyridyl, pyrimidinyl,pyrazinyl, benzimidazolyl, indolyl, and purinyl. Heteroaryl substituentscan be attached at a carbon atom or through, the heteroatom.

The term “halo” shall include iodo, bromo, chloro and fluoro.

The term “substituted” shall be deemed to include multiple degrees ofsubstitution by a named substitutent. Where multiple substituentmoieties are disclosed or claimed, the substituted compound can beindependently substituted by one or more of the disclosed or claimedsubstituent moieties, singly or plurally. By independently substituted,it is meant that the (two or more) substituents can be the same ordifferent.

The present invention also includes protected derivatives of compoundsdisclosed herein. For example, when compounds of the present inventioncontain groups such as hydroxyl or carbonyl, these groups can beprotected with a suitable protecting group. A comprehensive list ofsuitable protective groups can be found in T. W. Greene, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, Inc. 1981, thedisclosure of which is incorporated herein by reference in its entirety.The protected derivatives of compounds of the present invention can beprepared by methods well known in the art.

The compounds of the present invention may have asymmetric centers,chiral axes, and chiral planes (as described in: E. L. Eliel and S. H.Wilen, Stereochemistry of Carbon Compounds, John Wiley & Sons, New York,1994, pages 1119-1190), and occur as racemates, racemic mixtures, and asindividual diastereomers, with all possible isomers and mixturesthereof, including optical isomers, being included in the presentinvention. In addition, the compounds disclosed herein may exist astautomers and both tautomeric forms are intended to be encompassed bythe scope of the invention, even though only one tautomeric structure isdepicted. For example, any claim to compound A below is understood toinclude tautomeric structure B, and vice versa, as well as mixturesthereof.

When any variable (e.g. R¹, R², R³ etc.) occurs more than one time inany constituent, its definition on each occurrence is independent atevery other occurrence. Also, combinations of substituents and variablesare permissible only if such combinations result in stable compounds.Lines drawn into the ring systems from substituents indicate that theindicated bond may be attached to any of the substitutable ring carbonatoms. If the ring system is polycyclic, it is intended that the bond beattached to any of the suitable carbon atoms on the proximal ring only.

It is understood that substituents and substitution patterns on thecompounds of the instant invention can be selected by one of ordinaryskill in the art to provide compounds that are chemically stable andthat can be readily synthesized by techniques known in the art, as wellas those methods set forth below, from readily available startingmaterials. If a substituent is itself substituted with more than onegroup, it is understood that these multiple groups may be on the samecarbon or on different carbons, so long as a stable structure results.The phrase “optionally substituted with one or more substituents” shouldbe taken to be equivalent to the phrase “optionally substituted with atleast one substituent” and in such cases the preferred embodiment willhave from zero to three substituents.

In choosing compounds of the present invention, one of ordinary skill inthe art will recognize that the various substituents, i.e. R¹, R² and R³are to be chosen in conformity with well-known principles of chemicalstructure connectivity.

Representative compounds of the present invention typically displaysubmicromolar affinity for alpha and/or beta estrogen receptors, andpreferably agonize the beta estrogen receptor. Compounds of thisinvention are therefore useful in treating mammals suffering fromdisorders related to estrogen functioning.

The compounds of the present invention are available in racemic form oras individual enantiomers. For convenience, some structures aregraphically represented as a single enantiomer but, unless otherwiseindicated, is meant to include both racemic and enantiomerically pureforms. Where cis and trans stereochemistry is indicated for a compoundof the present invention, it should be noted that the stereochemistryshould be construed as relative, unless indicated otherwise. Forexample, a (+) or (−) designation should be construed to represent theindicated compound with the absolute stereochemistry as shown.

Racemic mixtures can be separated into their individual enantiomers byany of a number of conventional methods. These include, but are notlimited to, chiral chromatography, derivatization with a chiralauxiliary followed by separation by chromatography or crystallization,and fractional crystallization of diastereomeric salts. Deracemizationprocedures may also be employed, such as enantiomeric protonation of apro-chiral intermediate anion, and the like.

The fused five-membered triazole ring contains three nitrogen atoms, andthus tautomeric (R² is hydrogen) and positional (R² is a non-hydrogengroup) isomers are possible. These isomeric forms, as shown below, arecontemplated to fall within the scope of the present invention:

The compounds of the present invention can be used in combination withother agents useful for treating estrogen-mediated conditions. Theindividual components of such combinations can be administeredseparately at different times during the course of therapy orconcurrently in divided or single combination forms. The instantinvention is therefore to be understood as embracing all such regimes ofsimultaneous or alternating treatment and the term “administering” is tobe interpreted accordingly. It will be understood that the scope ofcombinations of the compounds of this invention with other agents usefulfor treating estrogen-mediated conditions includes in principle anycombination with any pharmaceutical composition useful for treatingdisorders related to estrogen functioning.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration;the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician,veterinarian or clinician can readily determine and prescribe theeffective amount of the drug required to prevent, counter or arrest theprogress of the condition.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as ‘carrier’ materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

The pharmaceutically acceptable salts of the compounds of this inventioninclude the conventional non-toxic salts of the compounds of thisinvention as formed inorganic or organic acids. For example,conventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric,nitric and the like, as well as salts prepared from organic acids suchas acetic, propionic, succinic, glycolic, stearic, lactic, malic,tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,glutamic, benzoic, salicylic, sulfanilic, 2-acetoxy-benzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic,trifluoroacetic and the like. The preparation of the pharmaceuticallyacceptable salts described above and other typical pharmaceuticallyacceptable salts is more fully described by Berg et al., “PharmaceuticalSalts,” J. Pharm. Sci., 1977:66:1-19, hereby incorporated by reference.The pharmaceutically acceptable salts of the compounds of this inventioncan be synthesized from the compounds of this invention which contain abasic or acidic moiety by conventional chemical methods. Generally, thesalts of the basic compounds are prepared either by ion exchangechromatography or by reacting the free base with stoichiometric amountsor with an excess of the desired salt-forming inorganic or organic acidin a suitable solvent or various combinations of solvents. Similarly,the salts of the acidic compounds are formed by reactions with theappropriate inorganic or organic base.

In the schemes and examples below, various reagent symbols andabbreviations have the following meanings:

-   -   AcOH: Acetic Acid    -   AgOAc: Silver acetate    -   AlCl₃: Aluminum chloride    -   AIBN: 2,2-azobisisobutyronitrile    -   BBr₃: Boron Tribromide    -   BnNH₂: Benzylamine    -   BrCH₂CH₂F: 1-Bromo-2-fluoroethane    -   BrCH₂CH₂OBn: 1-Bromo-2-benzyloxyethane    -   CCl₄: Carbon tetrachloride    -   CH₂Cl₂: Dichloromethane    -   CuBr: Copper Bromide    -   CuCN: Copper cyanide    -   CuI: Copper Iodide    -   DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene    -   DBN: 1,5-diazabicyclo[4.3.0]non-5-ene    -   DIEA: N,N-Diisopropylethylamine    -   DMAC: N,N-Dimethylacetamide    -   DMAP: 4-(Dimethylamino)pyridine    -   DMF: Dimethylformamide    -   EtOH: Ethanol    -   Et₃N: Triethylamine    -   EtSH: ethanethiol    -   EVK: Ethyl vinyl ketone    -   HCl: Hydrochloric acid    -   HOAc: Acetic Acid    -   K₂CO₃: Potassium carbonate    -   KI: Potassium iodide    -   KN(TMS)₂: Potassium bis(trimethylsilyl)amide    -   LiCl: Lithium chloride    -   LDA: Lithium Dimethylamide    -   LiN(TMS)₂: Lithium bis(trimethylsilyl)amide    -   Me₂CO₃: Methyl carbonate    -   MeCN: Methyl cyanide    -   MeOH: Methanol    -   MFSDA: methyl (fluorosulfonyl)difluoroacetate    -   MsCl: Mesyl chloride    -   MVK: Methyl vinyl ketone    -   NaH: Sodium hydride    -   NaI: Sodium iodide    -   NaNO₂: Sodium nitrite    -   NaOH: Sodium hydroxide    -   NaOMe: Sodium methylate    -   NaOt-Bu: Sodium t-butoxide    -   NCCO₂Et: Ethyl cyanoformate    -   NBS: N-Bromo Succinimide    -   NCS: N-Chloro Succinimide    -   NIS: N-IodoSuccinimide    -   NMO: N-methylmorpholine N-oxide    -   NMP: M-Methyl-2-pyrrolidone    -   PdCl₂(PPh₃)₂: Bis(triphenylphosphine)palladium(II) chloride    -   PdCl₂(dppf).CH₂Cl₂:        [1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium (II)    -   Pd₂(dba)₃: Tris(dibenzylideneacetone)dipalladium (0)    -   Pd(OAc)₂: Palladium acetate    -   Pd(PPh₃)₄: Tetrakis(triphenylphosphine)palladium(0)    -   PhB(OH)₂: Phenyl boronic acid    -   PhCH₃: Toluene    -   PhH: Benzene    -   PhMe: Toluene    -   PMB-Cl: Paramethoxybenzyl chloride    -   SEM-Cl: 2-(Trimethylsilyl)ethoxymethyl chloride    -   SMe₂: Dimethyl sulfide    -   SnMe₄: Tetramethyltin    -   Tf₂O: Triflic anhydride    -   THF: Tetrahydrofuran    -   TsOH: p-Toluenesulfonic acid    -   TPAP: Tripropylammonium perruthenate    -   XANTPHOS: 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

The novel compounds of the present invention can be prepared accordingto the procedures of the following schemes and examples, usingappropriate materials, and are further exemplified by the followingspecific examples. The compounds illustrated in the examples are not,however, to be construed as forming the only genus that is considered asthe invention. The following examples further illustrate details for thepreparation of the compounds of the present invention. Those skilled inthe art will readily understand that known variations of the conditionsand processes of the following preparative procedures can be used toprepare these compounds. All temperatures are degrees Celsius unlessotherwise noted.

The compounds of the present invention are prepared according to thegeneral methods outlined in Schemes I-XI. In these schemes, R^(I)represents R¹ or a precursor thereof; R^(Ia) and R^(Ib) representnon-hydrogen values of R¹, or precursors thereof; R^(II) represents R⁵or a precursor thereof; R^(IIIa) and R^(IIIb) represent non-hydrogenvalues of R³ and/or R⁴, or precursors thereof; R^(IV) represents OR^(a)and NR^(a)R^(a); R^(V) represents hydrogen, a C₁₋₅ alkyl group or asubstituted C₁₋₅ alkyl group; R^(O) and R^(P) independently representhydrogen or an N-protecting group for an aniline nitrogen such as acetylor benzyl; R^(M) represents a carboxyl esterifying group such as methyl,ethyl, allyl or benzyl; R^(Q) represents hydrogen or a N-protectinggroup for a benzotriazole group; R^(N) represents hydrogen or aremovable protecting group for a phenolic hydroxyl such as methyl,methoxymethyl or benzyl; R^(F) represents methyl, trifluoromethyl,nonafluorobutyl, phenyl or tolyl; Y represents a displaceable leavinggroup such as fluoro, chloro, bromo, iodo, methanesulfonyloxy,p-toluenesulfonyloxy, trifluoromethylsulfonyloxy and the like or aprecursor thereof such as hydroxyl, benzyloxy or acetoxy; and Zrepresents hydrogen or a removable aryl blocking group such as chloro orbromo. Other R groups are defined in the schemes in which they appear.

The final compounds of the present invention are synthesized fromsubstituted indanone compounds which are prepared by the methodsoutlined in Schemes I-IV. The starting materials for the synthesis ofScheme I are 5-amino-1-indanone derivatives (1), which are either knowncompounds or are prepared by conventional methods known in the art. Instep 1 of Scheme I, a protected 5-amino-1-indanone (1) is reacted with acarboxylating reagent such as ethyl cyanoformate or ethyl chloroformatein the presence of base to provide the beta-ketoester (2). In step 2,the beta-ketoester (2) is then reacted with an alkylating agentL-CH₂CH₂—Y, where L represents a displaceable leaving group, in thepresence of a base to give intermediate (3). In the case where Y alsorepresents a displaceable leaving group, the relative reactivities ofthe two groups are appropriately chosen so that L is the more easilydisplaced group. In step 3, the carboxyl group of intermediate (3) isremoved by hydrolysis or other cleavage of the ester followed bydecarboxylation to give (4). Step 4 represents an alternativeintroduction of the moiety —CH₂CH₂—Y. In this case the substitution isaccomplished by a reductive alkylation reaction wherein (1) is reactedwith a substituted aldehyde Y—CH₂CHO under basic conditions followed byhydrogenation of the resulting alkylidene intermediate. In this instanceY is most appropriately a precursor group which can be converted to adisplaceable leaving group at a later point in the synthesis.Alternatively, introduction of the moiety —CH₂CH₂—Y can be accomplishedby reacting indanone (1) with an alkylating agent L-CH₂CH₂—Y, where Lrepresents a displaceable leaving group, in the presence of a base togive (4). In the case where Y also represents a displaceable leavinggroup, the relative reactivities of the two groups are appropriatelychosen so that L is the more easily displaced group.

Representative reagents and reaction conditions indicated in Scheme I assteps 1-4 are as follows:

Step 1 i) LiN(TMS)₂, THF, −78 to 40° C. R^(M) = Et ii) NCCO₂Et, −78° C.to rt Me₂CO₃, NaH, PhH, 60° C. R^(M) = Me Step 2 BrCH₂CH₂F, K₂CO₃, KI,DMAC, 65° C. Y = F BrCH₂CH₂OBn, K₂CO₃, KI, DMAC, 60-100° C. Y = OBn Step3 NaOH, H₂O, MeOH, THF 0 to 40° C. or 6N HCl, HOAc, 90-100° C., Step 4BnOCH₂CHO, NaOMe, MeOH, H₂, Pd/C Y = OBn (HOCH₂CHO)₂, NaOMe, MeOH, H₂,Pd/C Y = OH

The synthesis of Scheme II is analogous to that of Scheme I but startswith 5-alkoxy-1-indanones (5) to prepare2-substituted-5-alkoxy-1-indanones (8). The 5-alkoxy-1-indanone startingmaterials for Scheme 2 are either known compounds or can be prepared byconventional methods known in the art.

Scheme III describes the synthesis of triazolo-indanones (13), which arethe starting materials for Scheme IV. The starting materials for thesynthesis of Scheme III are protected 5-amino-1-indanone derivatives(1a), which are either known compounds or are prepared by conventionalmethods known in the art. In step 1 of Scheme III, compound (1a) isnitrated by conventional means to provide nitro compound (9). Removal ofthe protecting group R^(O) from (9) in step 2 yields the nitro-anilinederivative (10). In step 3, reduction of the nitro group of (10)provides the diamino compound (11). Diazotization (step 4) of the4,5-diamino-indanone (11) produces the triazolo-indanone (12). The fusedtriazole ring of (12) is N-protected using any of a number of well knowngroups represented by R^(Q). Since the fused heteroaryl ring containsthree nitrogen atoms, positional isomers as indicated by the structures(13a), (13b) and (13c) are possible. These isomers can be used asmixtures or they can be separated and used independently in thefollowing steps. Structure (13) represents these possibilities.

Step 1 90% HNO₃, −78 to 0° C. Step 2 6N HCl, MeOH, reflux R^(o) = AcStep 3 H₂ (1 atm), 10% Pd/C, KOAc, EtOAc Step 4 NaNO₂, HCl, H₂O, EtOH,0° C. Step 5 SEM-Cl, NaH, DMF, 0° C. to rt R^(Q) = SEM PMB-Cl, NaH, DMF,0° C. to rt R^(Q) = PMB

The synthesis of Scheme IV is analogous to that of Scheme I but startswith triazolo-indanones (13) to produce2-substituted-4,5-triazolo-1-indanones (17). The triazolo-indanones (13)are prepared according to Scheme III.

Scheme V illustrates a method for constructing the pentacyclic3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-onecompounds of the present invention. In step 1, the2-substituted-1-indanone (4) reacts with a vinyl ketone in the presenceof base to give the diketone (18). The diketone is then cyclized (step2) under basic or acidic conditions to provide the tetrahydrofluorenoneproduct (19). In step 3, the ethylidene bridge is formed by an internalalkylation reaction in the presence of a base and/or with heating toproduce (20). Conversion of Y to a reactive leaving group may berequired prior to or in conjunction with this step. Step 4 is anoptional protection, deprotection, or deprotection-reprotection step ofthe nitrogen which may be carried-out on compound (20) to giveintermediate (21) depending on the desired R^(O) group. In the casewhere R^(I)═H in intermediate (21), a variety of non-hydrogen R^(I)groups can be introduced at this point in the synthesis as describedfurther below in Scheme VIII. In step 5, indanone (21) undergoesnitration to produce (22). When compound (21) possesses an unsubstituted6-position (Z=H), a regioisomeric nitro compound may also form which canbe separated from the desired product by conventional means, for examplechromatography or crystallization. Reduction of the nitro group of (22)in step 6 yields the amino compound (23). In step 7, diazotization of(23) provides the triazolo compound (24). In the case where Z representsa non-hydrogen aryl blocking group in intermediate (24), it is removedin step 8 to provide the final compound (25). In the case where R^(O) isa protecting group, a deprotection step may precede, accompany, orfollow the removal of Z.

Representative reagents and reaction conditions indicated in Scheme V assteps 1-8 are as follows:

Step 1 MVK, NaOMe, MeOH, rt to 60° C. or R^(I) = H MVK, DBN, THF, rt to60° C. EVK, NaOMe, MeOH, rt to 60° C. R^(I) = Me Step 2 pyrrolidine,HOAc, PhMe, 60-85° C. or NaOH, H₂O, MeOH or EtOH, rt to 85° C. or 6NHCl, HOAc, 90-100° C. or TsOH—H₂O, PhMe, 60-100° C. Step 3 LiCl, DMF,150° C. Y = F i) BBr₃, CH₂Cl₂, −78° C. Y = F ii) KN(TMS)₂, THF, −78° C.pyridine-HCl, 190° C. Y = OBn i) NaOMe, MeOH Y = OAc ii) MsCl, Et₃N,CH₂Cl₂ iii) LDA, THF, −78° C. to rt Step 4 i) pyridine-HCl, 180-195° C.for R^(O) = Bn, R^(P) = Bn ii) AcCl, K₂CO₃, CH₂Cl₂ to R^(O) = Ac, R^(P)= H Step 5 2,3,5,6-tetrabromo-4-methyl-4 nitrocyclohexa- 2,5-dienone,TFA, rt or NaNO₃, TFA, rt to 80° C. Step 6 H₂ (1 atm), 10% Pd/C, KOAc,MeOH, EtOAc Step 7 NaNO₂, HCl, H₂O, EtOH, 0° C. Step 8 H₂ (1 atm), 20%Pd(OH)₂/C, 5% Pd/CaCO₃, for Z = Cl DMF

Scheme VI illustrates an alternative method for constructing thepentacyclic3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-onecompounds of the present invention starting with a2-substituted-5-alkoxy-1-indanone (8) from Scheme II. Steps 1-3 proceedanalogously to the corresponding steps in Scheme V to produce thetetrahydrofluorenone (28). In step 4, the protecting group R^(N) isremoved from the phenol hydroxyl. In certain cases, this deprotectionwill conveniently occur during step 3 rendering a separate deprotectionin step 4 unnecessary. Reaction of phenol (29) with a sulfonylatingagent in step 5 yields the sulfonate intermediate (30). In step 6, thesulfonate (30) is converted to the aniline derivative (21) in apalladium catalyzed amidation reaction. Such amidation reactions arewell known in the art (see for example J. Am. Chem. Soc. 2003, 125,6653-6655; J. Org. Chem. 2003, 68, 9563-9573; J. Org. Chem. 2000, 65,1158-1174). Depending on the desired R^(O) group, a protection,deprotection, or deprotection-reprotection of the nitrogen may becarried-out on compound (21). In the case where R^(I)═H in intermediate(21), a variety of non-hydrogen R^(I) groups can be introduced at thispoint in the synthesis as described further below in Scheme VIII.Compound (21) is then converted to the final compound (25) by themethods previously described in Scheme V.

Representative reagents and reaction conditions indicated in Scheme V assteps 4-6 are as follows:

Step 4 LiCl, DMF, 150° C. or R^(N) = Me BBr₃, CH₂Cl₂, −78° C. to rt Step5 Tf₂O, EtN(i-Pr)₂, CH₂Cl₂, 0° C. to rt R^(F) = CF₃ Step 6 Pd₂(dba)₃,XANTPHOS, Cs₂CO₃, R^(O) = Ac MeCONH₂, PhMe, 80-100° C. Pd(OAc)₂,(o-biphenyl)P(t-Bu)₂, NaOt-Bu, R^(O) = Bn BnNH₂, PbMe, rt to 80° C.Pd(OAc)₂, 2-[(Cy)₂P]-2′,4′,6′-[tri-i-Pr]-1,1′-biphenyl R^(O) = K₂CO₃,PhB(OH)₂, H₂NCO₂t-Bu, CO₂tBu t-BuOH, rt to 110° C.

Scheme VII illustrates an alternative method for constructing thepentacyclic3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-onecompounds of the present invention starting with a2-substituted-4,5-triazolo-1-indanone (17) from Scheme IV. Steps 1-3proceed analogously to the corresponding steps in Scheme V to producethe tetrahydrofluorenone (33). In the case where R^(I)═H in intermediate(33), a variety of non-hydrogen R^(I) groups can be introduced at thispoint in the synthesis in a manner analogous to that described furtherbelow in Scheme VIII. In the case where Z represents a non-hydrogen arylblocking group in intermediate (33), it is removed in step 4 to providecompound (34). This step proceeds analogously to step 8 in Scheme V.Removal of the R^(Q) protecting group may precede, accompany, or followthe removal of Z. In Scheme VII the later possibility is illustrated.

Scheme VIII shows a method for the introduction of a non-hydrogen R^(I)group onto a C4-unsubstituted (R^(I)═H) tetrahydrofluorenoneintermediate (21a), which itself is prepared according to Scheme V orScheme VI. Enone (21a) undergoes chlorination, bromination, oriodination (step 1) to afford the 4-halo intermediates (21b).Intermediates (21b) are converted by established methods (step 2) into avariety of new derivatives (21c) wherein R^(Ib) is, inter alia, analkyl, alkenyl, alkynyl, aryl, heteroaryl or arylalkyl group. In certaincases the two steps can be conveniently carried-out in a “one-pot”sequence making the isolation of (21b) unnecessary. If the group R^(Ib)is, or contains, a functional group capable of further modification,such modifications can be carried out to produce additional derivatives.For example, if R^(Ib) is an alkenyl group, it can be reduced bycatalytic hydrogenation to an alkyl group. Intermediates (21b) and (21c)are converted to final compounds (25a) and (25b) respectively by theprocedures previously described in Scheme V. In an analogous fashion, anon-hydrogen R^(I) group can be introduced onto a C4-unsubstituted(R^(I)═H) intermediate (33) prepared according to Scheme VII.

Representative reagents and reaction conditions indicated in Scheme V assteps 1-2 are as follows:

Step 1 NCS, DMF, rt to 50° C. R^(Ia) = Cl Br₂, NaHCO₃, CH₂Cl₂ or CCl₄,0° C. to rt or R^(Ia) = Br NIS, DMF, 70 to 100° C. or R^(Ia) = I I₂,NaHCO₃, H₂O, CH₂Cl₂, rt Step 2 FSO₂CF₂CO₂Me, CuI, EtN(i-Pr)₂, DMF, 70 toR^(Ib) = CF₃ 100° C. R^(Ib)SnBu₃, PdCl₂(PPh₃)₂, PhMe, 100-110° C. orR^(Ib) = R^(Ib)SnBu₃, Pd(PPh₃)₄, PhMe, 100° C. or alkenyl, R^(Ib)B(OH)₂,PdCl₂(PPh₃)₂, Cs₂CO₃, DMF, 100° C. aryl or or R^(Ib)B(OH)₂, Pd(PPh₃)₄,aq Na₂CO₃, PhMe, heteroaryl 80° C. (R^(Ib))₃B, PdCl₂(dppf)•CH₂Cl₂,R^(Ib) = alkyl Ph₃As, Cs₂CO₃, H₂O, THF, DMF, 60° C.R^(Ib)Sn(CH₂CH₂CH₂)₃N, Pd(PPh₃)4, R^(Ib) = PhMe, 100° C. alkenyl, alkylor arylalkyl CuCN, NMP, 160° C. R^(Ib) = CN

Scheme IX illustrates a variation of the syntheses shown in Scheme I andScheme V which allows for introduction of the R^(II) substituent. Instep 1 of Scheme IX indanone (1) is reacted with a substituted aldehydeY—CH₂CHO under basic conditions and the alkylidene intermediate (35) isobtained. This step is similar to step 4 of Scheme I except that thereduction step is omitted. In this instance Y is most appropriately aprecursor group which can later be converted to a displaceable leavinggroup. Introduction of the R^(II) substituent is accomplished in step 2by reaction of (35) with an appropriate organometallic species to give(36) via a 1,4-conjugate addition reaction. Indanone (36) is thenconverted to the final compound (37) by the procedures previouslydescribed in Scheme V.

Representative reagents and reaction conditions indicated in Scheme IXas steps 1-2 are as follows:

Step 1 BnOCH₂CHO, KOH, MeOH or Y = OBn i) LiN(TMS)₂, THF, −78° C. to rtii) BnOCH₂CHO iii) MsCl, Et₃N, CH₂Cl₂ Step 2 R^(II)MgBr, CuBr•SMe₂, THF−78° C. to rt or R^(II) ₂CuLi, THF −78° C. to rtFinal compounds bearing substituents at the 10-position are prepared bythe methods summarized in Scheme X. Intermediate (38), where R^(Q)represents hydrogen or a nitrogen protecting group, is oxidized byN-halosuccinimide reagents and the like (step 1) to afford the 10-haloproducts (39). A final deprotection, if needed, then provides the finalcompounds (40). The 10-halo compounds (39) undergo displacementreactions with suitable nucleophilic reagents (step 2) to affordadditional products (41). A final deprotection, if needed, then providesthe final compounds (42). If desired, this methodology can be extendedto the preparation of 10,10-disubstituted products. The 10-oxo product(43) is available by potassium persulfate oxidation of (38). Reductionof (43) gives 10-hydroxy compounds (41, R^(IIIb)═OH). A finaldeprotection of (43), if needed, provides the final compounds (44).

Representative reagents and reaction conditions indicated in Scheme X assteps 14 are as follows:

Step 1 NCS, AIBN, CCl₄, rt to 80° C. R^(IIIa) = Cl NBS, AIBN, CCl₄, rtto 80° C. R^(IIIa) = Br Step 2 pyridine-HF, TFA, rt to 50° C. R^(IIIb) =F AgOAc, DMF, rt to 100° C. R^(IIIb) = OAc i) AgOAc, DMF, rt to 100° C.R^(IIIb) = OH ii) NaOH, H₂O, MeOH Step 3 K₂S₂O₈, H₂O, MeCN, rt to 80° C.Step 4 NaBH₄, MeOH, 0° C. to rt R^(IIIb) = OH

Modifications of the C-6 ketone of (38) are outlined in Scheme XI. Instep 1, the ketone is reacted with a hydroxylamine, alkoxylamine orhydrazine reagent to give the 6-imino products (45). Ketone (9) alsoreacts with ylide reagents (step 2) to afford 6-alkylidene derivatives(47). Deprotection, if needed, provides the final products (46) and(48).

Representative reagents and reaction conditions indicated in Scheme XIas steps 1-2 are as follows:

Step 1 NH₂OR^(a)•HCl, pyridine, rt to 60° C. R^(IV) = OR^(a)NH₂NR^(a)R^(a), EtOH, rt R^(IV) = NR^(a)R^(a) Step 2 Ph₃P⁺CH₂R^(VI)Br⁻,BuLi, THF, 0 to 50° C.

In Schemes I-XI, the various R groups often contain protected functionalgroups which are deblocked by conventional methods. The deblockingprocedure can occur at the last step or at an intermediate stage in thesynthetic sequence. Many well known protection-deprotection schemes canbe used to prevent unwanted reactions of functional groups contained inthe various R substituents.

The final compounds prepared according to Schemes I-XI have chiralcenters and can be resolved into the separate enantiomers by knownmethods, for example by chiral HPLC. Separation into the individualenantiomers can also be accomplished at a number of intermediate stagesin the synthesis.

The following specific examples, while not limiting, serve to illustratethe methods of preparation of the compounds of the present invention.

Example 1 Synthesis of(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one

Step 1: 6-chloro-5-methoxyindan-1-one

To a solution of 1-chloro-2-methoxybenzene (12.8 mL, 100 mmol) and3-chloropropanoyl chloride (10.5 mL, 110 mmol) in CH₂Cl₂ (100 mL) at 0°C. was added AlCl₃ (14.6 g, 110 mmol) portionwise during about 1 minute.After 30 minutes, sulfuric acid (300 mL) was poured slowly into thereaction mixture during about 3 minutes. The CH₂Cl₂ was removed byrotary evaporation under reduced pressure and the viscous residue wasstirred at 100° C. for 2 hours. After cooling to −50° C., the viscousreaction mixture was poured cautiously onto 1.5 L of ice and allowed tostand overnight. The mixture was filtered and the cake of crude productwas washed with water. The crude product was dissolved in 500 mL of 2%MeOH in CH₂Cl₂, dried over a mixture of Na₂CO₃ (˜10 g) and Na₂SO₄ (˜20g), filtered and concentrated under vacuum to give6-chloro-5-methoxyindan-1-one as an off-white solid.

Step 2: ethyl 6-chloro-5-methoxy-1-oxoindane-2-carboxylate

To a solution of 6-chloro-5-methoxyindan-1-one (27.6 g, 141 mmol) in THF(630 mL) at −78° C. was added a 1.0M solution of lithiumbis(trimethylsilyl)amide in THF (309 mL, 309 mmol) and then the solutionwas slowly warmed to ca −50° C. during 1 hour. After re-cooling to −78°C., ethyl cyanoformate (21.3 mL, 216 mmol) was introduced and thereaction mixture was allowed to warm to room temperature during 2 hours.After quenching with 300 mL of 1N HCl, most of the THF was removed byrotary evaporation under reduced pressure. The residual mixture wasextracted with EtOAc and the organic layer was washed with diluteaqueous NaHCO₃ and dried over Na₂SO₄. Filtration through a pad of silicaand removal of the solvent under reduced pressure gave ethyl6-chloro-5-methoxy-1-oxoindane-2-carboxylate as a brown oil.

Step 3: 6-chloro-2-(2-fluoroethyl)-5-methoxyindan-1-one

To a solution of ethyl 6-chloro-5-methoxy-1-oxoindane-2-carboxylate(crude product from the preceding step, ˜141 mmol) in anhydrousdimethylacetamide (540 mL) was added K₂CO₃ (39 g, 282 mmol), KI (46.8 g,282 mmol) and 1-bromo-2-fluoroethane (13.5 mL, 183 mmol) and the mixturewas stirred and heated at 65° C. for 6 hours. The reaction mixture wasdiluted with THF (540 mL) and water (540 mL) and then cooled to 0° C.and treated with 5N aqueous NaOH (84 mL, 423 mmol). After 2 hours at 0°C., the reaction was quenched with 1N aqueous HCl (˜450 mL). Most of theTHF was removed by rotary evaporation under reduced pressure and theaqueous residue was extracted with EtOAc. The organic layer was washedwith saturated NaHCO₃, dried over MgSO₄, filtered through a pad ofsilica gel and concentrated to give6-chloro-2-(2-fluoroethyl)-5-methoxyindan-1-one.

Step 4: 6-chloro-2-(2-fluoroethyl)-5-methoxy-2-(3-oxobutyl)indan-1-one

To a solution of 6-chloro-2-(2-fluoroethyl)-5-methoxyindan-1-one (34 g,140 mmol) in toluene (1500 mL) was addedN-[4-(trifluoromethyl)benzyl]cinchoninium bromide (13 g, 24 mmol) andthe mixture was stirred at room temperature for 30 minutes. Aftercooling to 0° C., methyl vinyl ketone (20 mL, 240 mmol) was addedfollowed by potassium hydroxide pellets (85%, 34 g, ˜52 mmol) and themixture was vigorously stirred for 90 minutes. The reaction mixture wasdiluted with dichloromethane (1000 mL), dried with MgSO₄ and filtered.The filtrate was filtered through a pad of silica gel, washing with Et₂Oand EtOAc. The filtrate was concentrated under reduced pressure and theresidue was chromatographed on silica gel (elution with 30% to 50%EtOAc/hexanes) to give6-chloro-2-(2-fluoroethyl)-5-methoxy-2-(3-oxobutyl)indan-1-one as ayellow oil. Analysis by chiral HPLC indicated an enantiomeric ratio ofapproximately 2:1 favoring the desired (2S)-enantiomer. Thisenantiomerically enriched material was utilized for the remainder of thesynthesis.

Step 5:6-chloro-9a-(2-fluoroethyl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one

To a solution of6-chloro-2-(2-fluoroethyl)-5-methoxy-2-(3-oxobutyl)indan-1-one (32 g,102 mmol) in toluene (1000 mL) were added acetic acid (7.0 mL, 120 mmol)and pyrrolidine (10 mL, 120 mmol) and the solution was heated at 95° C.for 2 hours. After cooling to room temperature, the reaction mixture wasdiluted with EtOAc (1000 mL), washed with water and saturated aqueousNaHCO₃, and dried over MgSO₄. Filtration through a pad of silica gel andremoval of the solvent under vacuum gave6-chloro-9a-(2-fluoroethyl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-oneas a solid.

Step 6: 3-chloro-2-hydroxygibba-1,3,4a(10a),4b-tetraen-6-one

To a mixture of6-chloro-9a-(2-fluoroethyl)-7-methoxy-1,2,9,9a-tetrahydro-3H-fluoren-3-one(18.5 g, 63 mmol) and lithium chloride (26.5 g, 630 mmol) was added DMF(250 mL) and the mixture was stirred and heated at 150° C. for 2 days.After cooling to room temperature, the reaction mixture was partitionedbetween EtOAc and water. The organic phase was washed with water (2×)and brine and dried over MgSO₄. Removal of the solvent under vacuum gavea solid which was partially dissolved in 5% MeOH/CH₂Cl₂ (300 mL) and theresulting suspension was filtered to give3-chloro-2-hydroxygibba-1,3,4a(10a),4b-tetraen-6-one as a brown solid.The filtrate was concentrated under vacuum and the residue was partiallydissolved in 200 mL of CH₂Cl₂ and filtered to give a second crop of3-chloro-2-hydroxygibba-1,3,4a(10a),4b-tetraen-6-one. The filtrate wasconcentrated under vacuum and the residue was flash chromatographed onsilica gel (elution with 10 to 100% EtOAc/hexanes) to give additional3-chloro-2-hydroxygibba-1,3,4a(10a),4b-tetraen-6-one.

Step 7: 3-chloro-6-oxogibba-1,3,4a(10a),4b-tetraen-2-ylTrifluoromethanesulfonate

To a suspension of 3-chloro-2-hydroxygibba-1,3,4a(10a),4b-tetraen-6-one(5.71 g, 21.2 mmol) in dichloromethane (80 mL) was addedN,N-diisopropylethylamine (4.0 mL, 23.2 mmol). The resulting brownsolution was cooled to 0° C. and trifluoromethanesulfonic anhydride (3.9mL, 23.2 mmol) was added. After 35 minutes, the reaction mixture wasdirectly loaded onto a silica gel column and chromatographed (elutionwith 10 to 100% EtOAc/hexanes) to give the product as a brown oil. Theoil was dissolved in dichloromethane and dried over MgSO₄. Evaporationunder vacuum gave a solid which was dissolved in toluene and thenevaporated under vacuum to give3-chloro-6-oxogibba-1,3,4a(10a),4b-tetraen-2-yltrifluoromethanesulfonate as a brown solid.

Step 8: N-[3-chloro-6-oxogibba-1,3,4a(10a),4b-tetraen-2-yl]acetamide

To a mixture of 3-chloro-6-oxogibba-1,3,4a(10a),4b-tetraen-2-yltrifluoromethanesulfonate (6.04 g, 15.4 mmol), cesium carbonate (11.01g, 33.9 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene(xantphos, 1.33 g, 2.31 mmol), tris(dibenzylideneacetone)dipalladium(0)[Pd₂(dba)₃, 0.704 g, 0.77 mmol] and acetamide (2.00 g, 33.9 mmol) wasadded toluene (77 mL). The reaction flask was capped and the stirredreaction mixture was heated at 100° C. under nitrogen. After heating for16 hours, additional xantphos (0.233 g, 0.403 mmol), Pd₂(dba)₃ (0.140 g,0.153 mmol) and acetamide (1.00 g, 16.9 mmol) were added. After heatingfor an additional 24 hours, the reaction mixture was cooled to roomtemperature, diluted with 5% MeOH/CH₂Cl₂, and filtered through a pad ofsilica gel. Evaporation under reduced pressure gave an oily brown solid.The solid was dissolved in dichloromethane (60 mL) andN,N-diisopropylethylamine (2.8 mL, 16 mmol) was added followed by acetylchloride (1.4 mL, 19 mmol). After 10 minutes, the solution was loadeddirectly onto a silica gel column and chromatographed (elution with 10to 100% EtOAc/hexanes) to giveN-[3-chloro-6-oxogibba-1,3,4a(10a),4b-tetraen-2-yl]acetamide as anorange solid.

Step 9:N-[3-chloro-6-oxo-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-2-yl]acetamide

To a solution ofN-[3-chloro-6-oxogibba-1,3,4a(10a),4b-tetraen-2-yl]acetamide (3.85 g,12.8 mmol) in DMF at 85° C. was added N-iodosuccinamide (4.00 g, 17.7mmol). After heating for 18 hours, the reaction mixture was cooled toroom temperature and diluted with DMF (160 mL). Copper(I) iodide (3.65g, 19.2 mmol), methyl (fluorosulfonyl)difluoroacetate (11.5 mL, 90 mmol)and N,N-diisopropylethylamine (15.8 mL, 90 mmol) were added and themixture was heated to 75° C. After 140 minutes, the reaction mixture wascooled to room temperature and filtered through a pad of silica gel,washing with EtOAc. The filtrate was partitioned between EtOAc and waterand the organic layer was washed with 5% aqueous NaHCO₃, water andbrine. Drying over MgSO₄ and evaporation under vacuum gave an oil whichwas chromatographed on silica gel (elution with 10 to 85% EtOAc/hexanes)to giveN-[3-chloro-6-oxo-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-2-yl]acetamideas an orange foam.

Step 10:2-amino-3-chloro-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-6-one

To a solution ofN-[3-chloro-6-oxo-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-2-yl]acetamide(3.80 g, 10.3 mmol) in 40 mL of acetic acid was added 6N hydrochloricacid (40 mL) and the solution was heated at 80° C. After 85 minutes, thereaction mixture was cooled to room temperature and partitioned betweenEtOAc and 5% aqueous NaHCO₃. Some orange precipitate formed which wasthoroughly extracted with EtOAc. The combined organic solutions werewashed with water and brine and dried over MgSO₄. Removal of the solventunder reduced pressure gave2-amino-3-chloro-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-6-oneas an orange solid.

Step 11:2-amino-3-chloro-1-nitro-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-6-one

To a solution of2-amino-3-chloro-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-6-one(2.9 g, 8.9 mmol) in trifluoroacetic acid (19 mL) was added2,3,5,6-tetrabromo-4-methyl-4-nitrocyclohexa-2,5-dienone and the thicksuspension was stirred at room temperature. After 70 minutes, themixture was cooled to 0° C. and filtered, washing with coldtrifluoroacetic acid. The filtrate was concentrated under vacuum and theresidue was partitioned between EtOAc/CH₂Cl₂ (10:1) and 10% aqueousK₂CO₃. The organic phase was washed thoroughly with 10% aqueous K₂CO₃followed by 5% aqueous NaHCO₃ and then brine. After drying over MgSO₄,evaporation of the solvent under vacuum gave2-amino-3-chloro-1-nitro-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-6-oneas a tan solid.

Step 12:1,2-diamino-3-chloro-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-6-one

To a suspension of2-amino-3-chloro-1-nitro-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-6-one(3.3 g, 8.9 mmol) in 1:1 MeOH/EtOAc (270 mL) was added potassium acetate(1.86 g, 19 mmol). The mixture was gently warmed to give a brownsolution which was hydrogenated at atmospheric pressure over 10%palladium on carbon (1.25 g). After 35 minutes, the mixture was filteredthrough NaHCO₃ on top of a pad of silica gel, washing with 5%MeOH/CH₂Cl₂. The filtrate was concentrated under reduced pressure andthe residue was chromatographed on silica gel (elution with 25% to 100%EtOAc in hexanes) to give1,2-diamino-3-chloro-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-6-oneas an orange solid.

Step 13:4-chloro-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one

To a suspension of1,2-diamino-3-chloro-5-(trifluoromethyl)gibba-1,3,4a(10a),4b-tetraen-6-one(2.1 g, 6.1 mmol) in ethanol (120 mL) were added water (2 mL) and 12Nhydrochloric acid (6.2 mL). The resulting orange solution was cooled to0° C. and 3M aqueous sodium nitrite (6.2 mL, 18.6 mmol) was added. After40 minutes, the solution was partitioned between EtOAc and water. Theorganic layer was washed with brine, dried over MgSO₄ and evaporatedunder vacuum to give4-chloro-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneas an orange solid.

Step 14:6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one

To a solution of4-chloro-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one(2.3 g, crude product from the preceding step, ˜6.1 mmol) in DMF (230mL) were added 20% Pd(OH)₂ on carbon (1 g) and 5% palladium on calciumcarbonate (1 g) and the mixture was hydrogenated at atmosphericpressure. After 29 hours, additional 20% Pd(OH)₂ on carbon (175 mg) and5% palladium on calcium carbonate (175 mg) were added. After 24 hoursmore, the mixture was filtered through a pad of Celite®, washingthoroughly with EtOAc. The filtrate was partitioned between EtOAc andwater which had been acidified with a small amount of 1N hydrochloricacid. The aqueous layer was thoroughly extracted with EtOAc and thecombined organic layers were washed with 1N hydrochloric acid, water andbrine. After drying over MgSO₄, the solvent was removed under reducedpressure to give an oily solid which was dissolved in dichloromethaneand evaporated to give a solid. Chromatography on silica gel (elutionwith 1:1 EtOAc/hexanes+0.1% HOAc followed by 99:99:2EtOAc/hexanes/methanol+0.1% HOAc) gave6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneas a pale yellow solid.

Step 15:(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one

6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta-[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one[1.8 g, (8R,10aS):(8S,10aR) enantiomeric ratio ˜2:1] was dissolved in1/1 ethanol/methanol (130 mL) and resolved by chiral HPLC on a 2.0×25 cmDaicel Chiralcel OJ column (4 mL injections, elution with 35%EtOH:Heptane at 7.5 L/min, fractions monitored at 310 nm). The purefractions containing the first enantiomer to elute (enantiomer A) werecombined and concentrated to give(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneas a white solid which had a negative rotation. The fractions containingthe second enantiomer to elute (enantiomer B) were combined andconcentrated to give(8S,10aR)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5d][1,2,3]triazol-7(8H)-oneas a solid which had a positive rotation.

Enantiomer A: [α]_(D)=−263° (MeOH).

¹H NMR (CD₃CN, 600 MHz): δ 1.61 (dddd, 1H), 1.74-1.79 (m, 1H), 1.95-2.05(m, 1H), 2.05 (dd, 1H), 2.12 (brd, 1H), 2.32-2.38 (m, 1H), 3.02 (dd,1H), 3.55 (d, 1H), 3.68 (d, 1H), 7.77 (d, 1H), 7.87 (dq, 1H).

Mass spectrum: (ESI) m/z=320 (M+H).

Examples 2-7

The following compounds were prepared using methods analogous to thosedescribed in the preceding examples:

2 R¹ = Br 6-bromo-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol- 7(8H)-one ¹H NMR(CDCl₃, 500 MHz): δ 1.79- 1.85 (m, 1H), 1.97-2.28 (m, 4H), 2.39-2.46 (m,1H), 3.42 (dd, 1H), 3.67-3.76 (m, 2H), 7.78-7.82 (m, 1H), 8.81 (d, 1H).

3 R¹ = Cl (8R, 10aS)-6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol- 7(8H)-one ¹H NMR(d⁶-DMSO, 600 MHz): δ 1.54-1.62 (m, 1H), 1.76-1.84 (m, 1H), 2.03-2.11(m, 2H), 2.13 (d, 1H), 2.28-2.37 (m, 1H), 3.15 (dd, 1H), 3.53 (d, 1H),3.65 (d, 1H), 7.92 (d, 1H), 8.35 (d, 1H). 4 R¹ = Ph (8R,10aS)-6-phenyl-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d]1,2,3[triazol- 7(8H)-one ¹H NMR(CDCl₃, 500 MHz): δ 1.9-2.0 (m, 1H), 2.0-2.2 (m, 2H), 2.20 (dd, 1H),2.31 (d, 1H), 2.4-2.5 (m, 1H), 3.29 (dd, 1H), 3.6-3.8 (m, 2H), 6.61 (d,1H), 7.0-7.6 (m, 6H).

5 R¹ = Cl (8R, 10aS)-6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol- 7(8H)-one oxime ¹HNMR (CD₃CN, 600 MHz): δ 1.55-1.61 (m, 1H), 1.83 (d, 1H), 1.86-1.93 (m,2H), 1.99 (dd, 1H), 2.22-2.30 (m, 1H), 3.45 (d, 1H), 3.57 (d, 1H), 4.09(dd, 1H), 7.79 (d, 1H), 8.39 (d, 1H). 6 R¹ = CF₃ (8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno-[4,5- d][1,2,3]triazol-7(8H)-oneoxime ¹H NMR (CD₃CN, 600 MHz): δ 1.53-1.59 (m, 1H), 1.70- 1.75 (m, 1H),1.73 (d, 1H), 1.83 (ddd, 1H), 1.95 (dd, 1H), 2.18- 2.25 (m, 1H), 3.43(d, 1H), 3.61 (d, 1H), 4.00 (dd, 1H), 7.72 (d, 1H), 7.78 (dd, 1H). 7 R¹= Ph (8R, 10aS)-6-phenyl-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol- 7(8H)-one oxime ¹HNMR (d⁶-DMSO, 600 MHz): δ 1.61-1.65 (m, 1H), 1.80-1.95 (m, 2H),1.95-2.00 (m, 1H), 3.2-3.6 (m, 2H), 3.97 (bs, 1H), 3.6-3.8 (m, 2H),7.0-7.6 (m, 7H).Estrogen Receptor Binding Assay

The estrogen receptor ligand binding assays are designed asscintillation proximity assays employing the use of tritiated estradioland recombinant expressed estrogen receptors. The full lengthrecombinant human ER-α and ER-β proteins are produced in a bacculoviralexpression system. ER-α or ER-β extracts are diluted 1:400 in phosphatebuffered saline containing 6 mM α-monothioglycerol. 200 μL aliquots ofthe diluted receptor preparation are added to each well of a 96-wellFlashplate. Plates are covered with Saran Wrap and incubated at 4° C.overnight.

The following morning, a 20 ul aliquot of phosphate buffered salinecontaining 10% bovine serum albumin is added to each well of the 96 wellplate and allowed to incubate at 4° C. for 2 hours. Then the plates arewashed with 200 μl of buffer containing 20 mM Tris (pH 7.2), 1 mM EDTA,10% Glycerol, 50 mM KCl, and 6 mM α-monothiolglycerol. To set up theassay in these receptor coated plates, add 178 ul of the same buffer toeach well of the 96 well plate. Then add 20 ul of a 10 nM solution of³H-estradiol to each well of the plate.

Test compounds are evaluated over a range of concentrations from 0.01 nMto 1000 nM. The test compound stock solutions should be made in 100%DMSO at 100× the final concentration desired for testing in the assay.The amount of DMSO in the test wells of the 96 well plate should notexceed 1%. The final addition to the assay plate is a 2 ul aliquot ofthe test compound which has been made up in 100% DMSO. Seal the platesand allow them to equilibrate at room temperature for 3 hours. Count theplates in a scintillation counter equipped for counting 96 well plates.

The compounds of Examples 1-7 exhibit binding affinities to the estrogenreceptor α-subtype in the range of IC₅₀=13 to >10,000 nm, and to theestrogen receptor 1-subtype in the range of IC₅₀=3 to 146 nm.

Pharmaceutical Composition

As a specific embodiment of this invention, 25 mg of compound of Example1, is formulated with sufficient finely divided lactose to provide atotal amount of 580 to 590 mg to fill a size 0, hard-gelatin capsule.

1. A method for treating an estrogen-mediated condition selected fromthe group consisting of uterine fibroid disease, hot flashes,perimenopausal depression and premenstrual syndrome in a mammal in needthereof, wherein the method comprises administering to the mammal: atherapeutically effective amount of a compound of the formula:

wherein X is O or N—OH, R¹ is hydrogen, fluoro, chloro, bromo, iodo orC₁₋₄alkyl, wherein the alkyl group is optionally substituted with 1, 2or 3 groups selected from the group consisting of fluoro, chloro andbromo, R² is hydrogen, R³ is hydrogen, R⁴ is hydrogen, and R⁵ ishydrogen; or a pharmaceutically acceptable salt thereof, or astereoisomer thereof; and a second active agent selected from the groupconsisting of an organic bisphosphonate, a cathepsin K inhibitor, anestrogen, an estrogen receptor modulator, an androgen receptormodulator, an inhibitor of osteoclast proton ATPase, an inhibitor ofHMG-CoA reductase, an integrin receptor antagonist, an osteoblastanabolic agent, calcitonin, Vitamin D, a synthetic Vitamin D analogue, aselective serotonin reuptake inhibitor and an aromatase inhibitor; or apharmaceutically acceptable salt or mixture thereof.
 2. The method ofclaim 1, wherein the second active agent is selected from the groupconsisting of an organic bisphosphonate, a cathepsin K inhibitor, anestrogen and an estrogen receptor modulator; or a pharmaceuticallyacceptable salt or mixture thereof.
 3. The method of claim 1, whereinthe compound is6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,or a pharmaceutically acceptable salt thereof, or a stereoisomerthereof.
 4. The method of claim 1, wherein the compound is(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneor a pharmaceutically acceptable salt thereof.
 5. The method of claim 1,wherein the compound is(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one.6. The method of claim 1, wherein: the compound is selected from thegroup consisting of:(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,(8R,10aS)-6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,(8R,10aS)-6-bromo-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,(8R,10aS)-6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneoxime, and(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneoxime; or a pharmaceutically acceptable salt thereof; and the secondactive agent is selected from the group consisting of an organicbisphosphonate, a cathepsin K inhibitor, an estrogen and an estrogenreceptor modulator.
 7. A method for treating an estrogen-mediatedcondition selected from the group consisting of uterine fibroid disease,hot flashes, perimenopausal depression and premenstrual syndrome in amammal in need thereof; wherein the method comprises administering tothe mammal: a therapeutically effective amount of a compound selectedfrom the group consisting of:6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,6-bromo-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneoxime,6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneoxime,6-phenyl-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,and6-phenyl-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneoxime; or a pharmaceutically acceptable salt thereof, or a stereoisomerthereof; and a second active agent selected from the group consisting ofan organic bisphosphonate, a cathepsin K inhibitor, an estrogen, anestrogen receptor modulator, an androgen receptor modulator, aninhibitor of osteoclast proton ATPase, an inhibitor of HMG-CoAreductase, an integrin receptor antagonist, an osteoblast anabolicagent, calcitonin, Vitamin D, a synthetic Vitamin D analogue, aselective serotonin reuptake inhibitor and an aromatase inhibitor; or apharmaceutically acceptable salt or mixture thereof.
 8. The method ofclaim 7, wherein: the compound is selected from the group consisting of:(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,(8R,10aS)-6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,(8R,10aS)-6-bromo-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,(8R,10aS)-6-chloro-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneoxime,(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneoxime,(8R,10aS)-6-phenyl-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one,and(8R,10aS)-6-phenyl-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-oneoxime; or a pharmaceutically acceptable salt thereof; and the secondactive agent is selected from the group consisting of an organicbisphosphonate, a cathepsin K inhibitor, an estrogen, an estrogenreceptor modulator, an androgen receptor modulator, an inhibitor ofosteoclast proton ATPase, an inhibitor of HMG-CoA reductase, an integrinreceptor antagonist, an osteoblast anabolic agent, calcitonin, VitaminD, a synthetic Vitamin D analogue, a selective serotonin reuptakeinhibitor and an aromatase inhibitor; or a pharmaceutically acceptablesalt or mixture thereof.
 9. The method of claim 7, wherein: the compoundis(8R,10aS)-6-(trifluoromethyl)-3,9,10,11-tetrahydro-8,10a-methanocyclohepta[1,2]indeno[4,5-d][1,2,3]triazol-7(8H)-one;and the second active agent is selected from the group consisting of anorganic bisphosphonate, a cathepsin K inhibitor, an estrogen and anestrogen receptor modulator; or a pharmaceutically acceptable salt ormixture thereof.
 10. The method of claim 1, wherein: the compound andthe second active agent are administered separately at different timesduring the course of therapy or concurrently in divided or singlecombination forms.